TY  - JOUR
AU  - Jovanović, Mirna
AU  - Stanković, Tijana
AU  - Stojković Burić, Sonja
AU  - Banković, Jasna
AU  - Dinić, Jelena
AU  - Ljujić, Mila
AU  - Pešić, Milica
AU  - Dragoj, Miodrag
PY  - 2022
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5041
AB  - Tspan14 is a transmembrane protein of the tetraspanin (Tspan) protein family. Different members of the Tspan family can promote or suppress tumor progression. The exact role of Tspan14 in tumor cells is unknown. Earlier, mutational inactivation of the TSPAN14 gene has been proposed to coincide with a low survival rate in NSCLC patients. This study aimed to investigate the correlation of TSPAN14 lack of function with clinicopathological features of NSCLC patients, and to elucidate the role TSPAN14 might have in NSCLC progression. TSPAN14 expression was lower in tumor cells than non-tumor cells in NSCLC patients’ samples. The decreased gene expression was correlated with a low survival rate of patients and was more frequent in patients with aggressive, invasive tumor types. Additionally, the role of decreased TSPAN14 expression in the metastatic potential of cancer cells was confirmed in NSCLC cell lines. The highly invasive NSCLC cell line (NCI-H661) had the lowest TSPAN14 gene and protein expression, whereas the NSCLC cell line with the highest TSPAN14 expression (NCI-H460) had no significant metastatic potential. Finally, silencing of TSPAN14 in these non-metastatic cancer cells caused an increased expression of matrix-degrading enzymes MMP-2 and MMP-9, followed by an elevated capacity of cancer cells to degrade gelatin. The results of this study propose TSPAN14 expression as an indicator of NSCLC metastatic potential and progression.
PB  - Basel : MDPI
T2  - Life
T1  - Decreased TSPAN14 Expression Contributes to NSCLC Progression
IS  - 9
VL  - 12
DO  - 10.3390/life12091291
SP  - 1291
ER  - 

@article{
author = "Jovanović, Mirna and Stanković, Tijana and Stojković Burić, Sonja and Banković, Jasna and Dinić, Jelena and Ljujić, Mila and Pešić, Milica and Dragoj, Miodrag",
year = "2022",
abstract = "Tspan14 is a transmembrane protein of the tetraspanin (Tspan) protein family. Different members of the Tspan family can promote or suppress tumor progression. The exact role of Tspan14 in tumor cells is unknown. Earlier, mutational inactivation of the TSPAN14 gene has been proposed to coincide with a low survival rate in NSCLC patients. This study aimed to investigate the correlation of TSPAN14 lack of function with clinicopathological features of NSCLC patients, and to elucidate the role TSPAN14 might have in NSCLC progression. TSPAN14 expression was lower in tumor cells than non-tumor cells in NSCLC patients’ samples. The decreased gene expression was correlated with a low survival rate of patients and was more frequent in patients with aggressive, invasive tumor types. Additionally, the role of decreased TSPAN14 expression in the metastatic potential of cancer cells was confirmed in NSCLC cell lines. The highly invasive NSCLC cell line (NCI-H661) had the lowest TSPAN14 gene and protein expression, whereas the NSCLC cell line with the highest TSPAN14 expression (NCI-H460) had no significant metastatic potential. Finally, silencing of TSPAN14 in these non-metastatic cancer cells caused an increased expression of matrix-degrading enzymes MMP-2 and MMP-9, followed by an elevated capacity of cancer cells to degrade gelatin. The results of this study propose TSPAN14 expression as an indicator of NSCLC metastatic potential and progression.",
publisher = "Basel : MDPI",
journal = "Life",
title = "Decreased TSPAN14 Expression Contributes to NSCLC Progression",
number = "9",
volume = "12",
doi = "10.3390/life12091291",
pages = "1291"
}

Jovanović, M., Stanković, T., Stojković Burić, S., Banković, J., Dinić, J., Ljujić, M., Pešić, M.,& Dragoj, M.. (2022). Decreased TSPAN14 Expression Contributes to NSCLC Progression. in Life
Basel : MDPI., 12(9), 1291.
https://doi.org/10.3390/life12091291

Jovanović M, Stanković T, Stojković Burić S, Banković J, Dinić J, Ljujić M, Pešić M, Dragoj M. Decreased TSPAN14 Expression Contributes to NSCLC Progression. in Life. 2022;12(9):1291.
doi:10.3390/life12091291 .

Jovanović, Mirna, Stanković, Tijana, Stojković Burić, Sonja, Banković, Jasna, Dinić, Jelena, Ljujić, Mila, Pešić, Milica, Dragoj, Miodrag, "Decreased TSPAN14 Expression Contributes to NSCLC Progression" in Life, 12, no. 9 (2022):1291,
https://doi.org/10.3390/life12091291 . .

TY  - CONF
AU  - Jovanović Stojanov, Sofija
AU  - Podolski-Renić, Ana
AU  - Jovanović, Mirna
AU  - Pešić, Milica
AU  - Stanković, Tijana
AU  - Dragoj, Miodrag
PY  - 2022
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5393
AB  - Неситноћелијски  карцином  плућа  је  најчешћи  облик  рака  плућа.  У  време  постављања  дијагнозе,  велики  проценат  пацијената  већ  има  развијене  метастазе  одговорне за изузетно високу стопу смртности. Фокална адхезиона киназа (FAK) и  матриксне  металопротеиназе  (MMP2  и  ММР9)  су  међу  кључним  молекулима  укљученим  у  процес  метастазирања.  Прекомерно  су  експримирани  у  већини  тумора, повећавајући инвазивни и метастатски капацитет  туморских ћелија. FAK  своју проинвазивну улогу делом остварује регулисањем производње и ослобађања 
ММР2 и ММР9. У овој студији је анализирана експресија ММР2 и ММР9 у односу  на  повећану  експресију  FAK-а  код  пацијената  са  неситноћелијским  карциномом  плућа.  Показано  је  да  истовремено  повећана  експресија  FAK  и  макар  једне  од  испитиваних  матриксних  металопротеиназа  негативно  утичу  на  преживљавање.  Стога  је  in  vitro  испитиван  антиинвазивни  и  антитуморски  ефекат  истовремене  циљане  инхибиције  FAK  и  ММР2/MMP9  одговарајућим  инхибиторима  малих  молекула.  Добијени  резултати  су  показали  да  истовремена  инхибиција  FAK  и  ММР2/MMP9  не  утиче  значајно  на  смањење  инвазивних  способности  туморских  ћелија  у  односу  на  појединачне  третмане  инхибиторима.  Насупрот  томе,  истовремена инхибиција FAK и ММР2/MMP9 има изражен антитуморски ефекат,  смањује вијабилност ћелија доводећи до апоптозе. На основу добијених података  може  се  закључити  да  би  истовремена  циљана  инхибиција  FAK  и  ММР2/MMP9  могла бити обећавајући терапијски приступ за неситноћелијски карцином плућа.
AB  - Nesitnoćelijski karcinom pluća je najčešći oblik raka pluća. U vreme postavljanja dijagnoze, veliki procenat pacijenata već ima razvijene metastaze odgovorne za izuzetno visoku stopu smrtnosti. Fokalna adheziona kinaza (FAK) i matriksne metaloproteinaze (MMP2 i MMR9) su među ključnim molekulima uključenim u proces metastaziranja. Prekomerno su eksprimirani u većini tumora, povećavajući invazivni i metastatski kapacitet tumorskih ćelija. FAK svoju proinvazivnu ulogu delom ostvaruje regulisanjem proizvodnje i oslobađanja MMR2 i MMR9. U ovoj studiji je analizirana ekspresija MMR2 i MMR9 u odnosu na povećanu ekspresiju FAK-a kod pacijenata sa nesitnoćelijskim karcinomom pluća. Pokazano je da istovremeno povećana ekspresija FAK i makar jedne od ispitivanih matriksnih metaloproteinaza negativno utiču na preživljavanje. Stoga je in vitro ispitivan antiinvazivni i antitumorski efekat istovremene ciljane inhibicije FAK i MMR2/MMP9 odgovarajućim inhibitorima malih molekula. Dobijeni rezultati su pokazali da istovremena inhibicija FAK i MMR2/MMP9 ne utiče značajno na smanjenje invazivnih sposobnosti tumorskih ćelija u odnosu na pojedinačne tretmane inhibitorima. Nasuprot tome, istovremena inhibicija FAK i MMR2/MMP9 ima izražen antitumorski efekat, smanjuje vijabilnost ćelija dovodeći do apoptoze. Na osnovu dobijenih podataka može se zaključiti da bi istovremena ciljana inhibicija FAK i MMR2/MMP9 mogla biti obećavajući terapijski pristup za nesitnoćelijski karcinom pluća.
PB  - Belgrade: Serbian Biological Society
C3  - Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia
T1  - Ispitivanje  matriksnih  metaloproteinaza  i  fokalne  adhezione kinaze kao farmakoloških meta kod nesitnoćelijskog karcinoma pluća
T1  - Испитивање матриксних металопротеиназа и фокалне адхезионе киназе као фармаколошких мета код неситноћелијског карцинома плућа
SP  - 331
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5393
ER  - 

@conference{
author = "Jovanović Stojanov, Sofija and Podolski-Renić, Ana and Jovanović, Mirna and Pešić, Milica and Stanković, Tijana and Dragoj, Miodrag",
year = "2022",
abstract = "Неситноћелијски  карцином  плућа  је  најчешћи  облик  рака  плућа.  У  време  постављања  дијагнозе,  велики  проценат  пацијената  већ  има  развијене  метастазе  одговорне за изузетно високу стопу смртности. Фокална адхезиона киназа (FAK) и  матриксне  металопротеиназе  (MMP2  и  ММР9)  су  међу  кључним  молекулима  укљученим  у  процес  метастазирања.  Прекомерно  су  експримирани  у  већини  тумора, повећавајући инвазивни и метастатски капацитет  туморских ћелија. FAK  своју проинвазивну улогу делом остварује регулисањем производње и ослобађања 
ММР2 и ММР9. У овој студији је анализирана експресија ММР2 и ММР9 у односу  на  повећану  експресију  FAK-а  код  пацијената  са  неситноћелијским  карциномом  плућа.  Показано  је  да  истовремено  повећана  експресија  FAK  и  макар  једне  од  испитиваних  матриксних  металопротеиназа  негативно  утичу  на  преживљавање.  Стога  је  in  vitro  испитиван  антиинвазивни  и  антитуморски  ефекат  истовремене  циљане  инхибиције  FAK  и  ММР2/MMP9  одговарајућим  инхибиторима  малих  молекула.  Добијени  резултати  су  показали  да  истовремена  инхибиција  FAK  и  ММР2/MMP9  не  утиче  значајно  на  смањење  инвазивних  способности  туморских  ћелија  у  односу  на  појединачне  третмане  инхибиторима.  Насупрот  томе,  истовремена инхибиција FAK и ММР2/MMP9 има изражен антитуморски ефекат,  смањује вијабилност ћелија доводећи до апоптозе. На основу добијених података  може  се  закључити  да  би  истовремена  циљана  инхибиција  FAK  и  ММР2/MMP9  могла бити обећавајући терапијски приступ за неситноћелијски карцином плућа., Nesitnoćelijski karcinom pluća je najčešći oblik raka pluća. U vreme postavljanja dijagnoze, veliki procenat pacijenata već ima razvijene metastaze odgovorne za izuzetno visoku stopu smrtnosti. Fokalna adheziona kinaza (FAK) i matriksne metaloproteinaze (MMP2 i MMR9) su među ključnim molekulima uključenim u proces metastaziranja. Prekomerno su eksprimirani u većini tumora, povećavajući invazivni i metastatski kapacitet tumorskih ćelija. FAK svoju proinvazivnu ulogu delom ostvaruje regulisanjem proizvodnje i oslobađanja MMR2 i MMR9. U ovoj studiji je analizirana ekspresija MMR2 i MMR9 u odnosu na povećanu ekspresiju FAK-a kod pacijenata sa nesitnoćelijskim karcinomom pluća. Pokazano je da istovremeno povećana ekspresija FAK i makar jedne od ispitivanih matriksnih metaloproteinaza negativno utiču na preživljavanje. Stoga je in vitro ispitivan antiinvazivni i antitumorski efekat istovremene ciljane inhibicije FAK i MMR2/MMP9 odgovarajućim inhibitorima malih molekula. Dobijeni rezultati su pokazali da istovremena inhibicija FAK i MMR2/MMP9 ne utiče značajno na smanjenje invazivnih sposobnosti tumorskih ćelija u odnosu na pojedinačne tretmane inhibitorima. Nasuprot tome, istovremena inhibicija FAK i MMR2/MMP9 ima izražen antitumorski efekat, smanjuje vijabilnost ćelija dovodeći do apoptoze. Na osnovu dobijenih podataka može se zaključiti da bi istovremena ciljana inhibicija FAK i MMR2/MMP9 mogla biti obećavajući terapijski pristup za nesitnoćelijski karcinom pluća.",
publisher = "Belgrade: Serbian Biological Society",
journal = "Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia",
title = "Ispitivanje  matriksnih  metaloproteinaza  i  fokalne  adhezione kinaze kao farmakoloških meta kod nesitnoćelijskog karcinoma pluća, Испитивање матриксних металопротеиназа и фокалне адхезионе киназе као фармаколошких мета код неситноћелијског карцинома плућа",
pages = "331",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5393"
}

Jovanović Stojanov, S., Podolski-Renić, A., Jovanović, M., Pešić, M., Stanković, T.,& Dragoj, M.. (2022). Ispitivanje  matriksnih  metaloproteinaza  i  fokalne  adhezione kinaze kao farmakoloških meta kod nesitnoćelijskog karcinoma pluća. in Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia
Belgrade: Serbian Biological Society., 331.
https://hdl.handle.net/21.15107/rcub_ibiss_5393

Jovanović Stojanov S, Podolski-Renić A, Jovanović M, Pešić M, Stanković T, Dragoj M. Ispitivanje  matriksnih  metaloproteinaza  i  fokalne  adhezione kinaze kao farmakoloških meta kod nesitnoćelijskog karcinoma pluća. in Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia. 2022;:331.
https://hdl.handle.net/21.15107/rcub_ibiss_5393 .

Jovanović Stojanov, Sofija, Podolski-Renić, Ana, Jovanović, Mirna, Pešić, Milica, Stanković, Tijana, Dragoj, Miodrag, "Ispitivanje  matriksnih  metaloproteinaza  i  fokalne  adhezione kinaze kao farmakoloških meta kod nesitnoćelijskog karcinoma pluća" in Knjiga sažetaka: Treći Kongres biologa Srbije: Osnovna i primenjena istraživanja: Metodika nastave; 2022 Sep 21-25; Zlatibor, Serbia (2022):331,
https://hdl.handle.net/21.15107/rcub_ibiss_5393 .

TY  - CONF
AU  - Jovanović Stojanov, Sofija
AU  - Dragoj, Miodrag
AU  - Jovanović, Mirna
AU  - Stojkovska, Jasmina
AU  - Stankovic, Tijana
AU  - Dinić, Jelena
AU  - Podolski-Renić, Ana
AU  - Stepanović, Ana
AU  - Obradović, Bojana
AU  - Pešić, Milica
PY  - 2021
UR  - https://www.eacr.org/login.php?referrer=%2Fconference%2FGoodbyeflatbiology2021virtual%2Fdigital-abstracts%2Fdetail%2F4208
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/4904
AB  - Glioblastoma (GMB) is the most common and aggressive primary malignant brain tumor. Median life expectancy with the only clinically approved treatment option, Stupp protocol, is 11-15 months. This protocol involves surgical resection followed by 6 weeks of radiation and chemotherapy and then 6 cycles of 5-day chemotherapy treatment and 23 days of recovery. The only approved chemotherapeutic drug currently used is temozolomide (TMZ) that improves patients' survival for 2.5 months compared to radiotherapy alone. Such limited therapeutic options could be partly due to the lack of appropriate glioblastoma models for testing novel drugs and new treatment modalities.  
Therefore we established a novel long-term 3D glioblastoma biomimicking model system that would enable optimal drug testing in clinically more relevant duration. Glioblastoma U87 cells were immobilized in alginate microtubes and cultivated for 28 days, initially under static conditions. Cell viability, morphology and aggregate formation were monitored under fluorescent and confocal microscopes upon double staining with calcein-AM/propidium iodide. Most importantly, we investigated the effects of two different TMZ treatment modalities on cell viability and expression of resistance-related genes, MGMT and ABCB1. All treatments with 100 μm TMZ started on day 7 (X=7). We compared 3-day subsequent treatment modality (day by day treatments, X+1) with protractive treatment modality (every 7th day, X+7). 
In established 3D model system, cells managed to grow for up to 28 days without propagation, formed aggregates and constantly increased their number. Both treatment modalities had the same effects on cell viability. However, three day treatment in a row led to a tremendous increase in the expression of resistance markers, which was significantly higher compared to protractive treatment modality.
	The results showed that our 3D model system is suitable for drug testing and revealed that protractive treatment modality could be more beneficial for GBM patients.
PB  - The European Association for Cancer Research
C3  - Goodbye Flat Biology: Next Generation Cancer Models; 2021 Oct 5-6; Virtual event, Worldwide
T1  - Evaluation of different temozolomide treatment modalities in a novel long-term 3D glioblastoma cell culture
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_4904
ER  - 

@conference{
author = "Jovanović Stojanov, Sofija and Dragoj, Miodrag and Jovanović, Mirna and Stojkovska, Jasmina and Stankovic, Tijana and Dinić, Jelena and Podolski-Renić, Ana and Stepanović, Ana and Obradović, Bojana and Pešić, Milica",
year = "2021",
abstract = "Glioblastoma (GMB) is the most common and aggressive primary malignant brain tumor. Median life expectancy with the only clinically approved treatment option, Stupp protocol, is 11-15 months. This protocol involves surgical resection followed by 6 weeks of radiation and chemotherapy and then 6 cycles of 5-day chemotherapy treatment and 23 days of recovery. The only approved chemotherapeutic drug currently used is temozolomide (TMZ) that improves patients' survival for 2.5 months compared to radiotherapy alone. Such limited therapeutic options could be partly due to the lack of appropriate glioblastoma models for testing novel drugs and new treatment modalities.  
Therefore we established a novel long-term 3D glioblastoma biomimicking model system that would enable optimal drug testing in clinically more relevant duration. Glioblastoma U87 cells were immobilized in alginate microtubes and cultivated for 28 days, initially under static conditions. Cell viability, morphology and aggregate formation were monitored under fluorescent and confocal microscopes upon double staining with calcein-AM/propidium iodide. Most importantly, we investigated the effects of two different TMZ treatment modalities on cell viability and expression of resistance-related genes, MGMT and ABCB1. All treatments with 100 μm TMZ started on day 7 (X=7). We compared 3-day subsequent treatment modality (day by day treatments, X+1) with protractive treatment modality (every 7th day, X+7). 
In established 3D model system, cells managed to grow for up to 28 days without propagation, formed aggregates and constantly increased their number. Both treatment modalities had the same effects on cell viability. However, three day treatment in a row led to a tremendous increase in the expression of resistance markers, which was significantly higher compared to protractive treatment modality.
	The results showed that our 3D model system is suitable for drug testing and revealed that protractive treatment modality could be more beneficial for GBM patients.",
publisher = "The European Association for Cancer Research",
journal = "Goodbye Flat Biology: Next Generation Cancer Models; 2021 Oct 5-6; Virtual event, Worldwide",
title = "Evaluation of different temozolomide treatment modalities in a novel long-term 3D glioblastoma cell culture",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_4904"
}

Jovanović Stojanov, S., Dragoj, M., Jovanović, M., Stojkovska, J., Stankovic, T., Dinić, J., Podolski-Renić, A., Stepanović, A., Obradović, B.,& Pešić, M.. (2021). Evaluation of different temozolomide treatment modalities in a novel long-term 3D glioblastoma cell culture. in Goodbye Flat Biology: Next Generation Cancer Models; 2021 Oct 5-6; Virtual event, Worldwide
The European Association for Cancer Research..
https://hdl.handle.net/21.15107/rcub_ibiss_4904

Jovanović Stojanov S, Dragoj M, Jovanović M, Stojkovska J, Stankovic T, Dinić J, Podolski-Renić A, Stepanović A, Obradović B, Pešić M. Evaluation of different temozolomide treatment modalities in a novel long-term 3D glioblastoma cell culture. in Goodbye Flat Biology: Next Generation Cancer Models; 2021 Oct 5-6; Virtual event, Worldwide. 2021;.
https://hdl.handle.net/21.15107/rcub_ibiss_4904 .

Jovanović Stojanov, Sofija, Dragoj, Miodrag, Jovanović, Mirna, Stojkovska, Jasmina, Stankovic, Tijana, Dinić, Jelena, Podolski-Renić, Ana, Stepanović, Ana, Obradović, Bojana, Pešić, Milica, "Evaluation of different temozolomide treatment modalities in a novel long-term 3D glioblastoma cell culture" in Goodbye Flat Biology: Next Generation Cancer Models; 2021 Oct 5-6; Virtual event, Worldwide (2021),
https://hdl.handle.net/21.15107/rcub_ibiss_4904 .

TY  - JOUR
AU  - Stanković, Tijana
AU  - Ranđelović, Teodora
AU  - Dragoj, Miodrag
AU  - Stojković Burić, Sonja
AU  - Fernández, Luis
AU  - Ochoa, Ignacio
AU  - Pérez-García, Victor M.
AU  - Pešić, Milica
PY  - 2021
UR  - https://linkinghub.elsevier.com/retrieve/pii/S136876462100011X
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4242
AB  - The poor response of glioblastoma to current treatment protocols is a consequence of its intrinsic drug resistance. Resistance to chemotherapy is primarily associated with considerable cellular heterogeneity, and plasticity of glioblastoma cells, alterations in gene expression, presence of specific tumor microenvironment conditions and blood-brain barrier. In an attempt to successfully overcome chemoresistance and better understand the biological behavior of glioblastoma, numerous tri-dimensional (3D) biomimetic models were developed in the past decade. These novel advanced models are able to better recapitulate the spatial organization of glioblastoma in a real time, therefore providing more realistic and reliable evidence to the response of glioblastoma to therapy. Moreover, these models enable the fine-tuning of different tumor microenvironment conditions and facilitate studies on the effects of the tumor microenvironment on glioblastoma chemoresistance. This review outlines current knowledge on the essence of glioblastoma chemoresistance and describes the progress achieved by 3D biomimetic models. Moreover, comprehensive literature assessment regarding the influence of 3D culturing and microenvironment mimicking on glioblastoma gene expression and biological behavior is also provided. The contribution of the blood-brain barrier as well as the blood-tumor barrier to glioblastoma chemoresistance is also reviewed from the perspective of 3D biomimetic models. Finally, the role of mathematical models in predicting 3D glioblastoma behavior and drug response is elaborated. In the future, technological innovations along with mathematical simulations should create reliable 3D biomimetic systems for glioblastoma research that should facilitate the identification and possibly application in preclinical drug testing and precision medicine.
PB  - Churchill Livingstone
T2  - Drug Resistance Updates
T1  - In vitro biomimetic models for glioblastoma-a promising tool for drug response studies
VL  - 55
DO  - 10.1016/j.drup.2021.100753
SP  - 100753
ER  - 

@article{
author = "Stanković, Tijana and Ranđelović, Teodora and Dragoj, Miodrag and Stojković Burić, Sonja and Fernández, Luis and Ochoa, Ignacio and Pérez-García, Victor M. and Pešić, Milica",
year = "2021",
abstract = "The poor response of glioblastoma to current treatment protocols is a consequence of its intrinsic drug resistance. Resistance to chemotherapy is primarily associated with considerable cellular heterogeneity, and plasticity of glioblastoma cells, alterations in gene expression, presence of specific tumor microenvironment conditions and blood-brain barrier. In an attempt to successfully overcome chemoresistance and better understand the biological behavior of glioblastoma, numerous tri-dimensional (3D) biomimetic models were developed in the past decade. These novel advanced models are able to better recapitulate the spatial organization of glioblastoma in a real time, therefore providing more realistic and reliable evidence to the response of glioblastoma to therapy. Moreover, these models enable the fine-tuning of different tumor microenvironment conditions and facilitate studies on the effects of the tumor microenvironment on glioblastoma chemoresistance. This review outlines current knowledge on the essence of glioblastoma chemoresistance and describes the progress achieved by 3D biomimetic models. Moreover, comprehensive literature assessment regarding the influence of 3D culturing and microenvironment mimicking on glioblastoma gene expression and biological behavior is also provided. The contribution of the blood-brain barrier as well as the blood-tumor barrier to glioblastoma chemoresistance is also reviewed from the perspective of 3D biomimetic models. Finally, the role of mathematical models in predicting 3D glioblastoma behavior and drug response is elaborated. In the future, technological innovations along with mathematical simulations should create reliable 3D biomimetic systems for glioblastoma research that should facilitate the identification and possibly application in preclinical drug testing and precision medicine.",
publisher = "Churchill Livingstone",
journal = "Drug Resistance Updates",
title = "In vitro biomimetic models for glioblastoma-a promising tool for drug response studies",
volume = "55",
doi = "10.1016/j.drup.2021.100753",
pages = "100753"
}

Stanković, T., Ranđelović, T., Dragoj, M., Stojković Burić, S., Fernández, L., Ochoa, I., Pérez-García, V. M.,& Pešić, M.. (2021). In vitro biomimetic models for glioblastoma-a promising tool for drug response studies. in Drug Resistance Updates
Churchill Livingstone., 55, 100753.
https://doi.org/10.1016/j.drup.2021.100753

Stanković T, Ranđelović T, Dragoj M, Stojković Burić S, Fernández L, Ochoa I, Pérez-García VM, Pešić M. In vitro biomimetic models for glioblastoma-a promising tool for drug response studies. in Drug Resistance Updates. 2021;55:100753.
doi:10.1016/j.drup.2021.100753 .

Stanković, Tijana, Ranđelović, Teodora, Dragoj, Miodrag, Stojković Burić, Sonja, Fernández, Luis, Ochoa, Ignacio, Pérez-García, Victor M., Pešić, Milica, "In vitro biomimetic models for glioblastoma-a promising tool for drug response studies" in Drug Resistance Updates, 55 (2021):100753,
https://doi.org/10.1016/j.drup.2021.100753 . .

TY  - JOUR
AU  - Dragoj, Miodrag
AU  - Stojkovska, Jasmina
AU  - Stanković, Tijana
AU  - Dinić, Jelena
AU  - Podolski-Renić, Ana
AU  - Obradović, Bojana
AU  - Pešić, Milica
PY  - 2021
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4294
AB  - Background: Various three-dimensional (3D) glioblastoma cell culture models have a limited duration of viability. Our aim was to develop a long-term 3D glioblastoma model, which is necessary for reliable drug response studies. Methods: Human U87 glioblastoma cells were cultured in alginate microfibers for 28 days. Cell growth, viability, morphology, and aggregation in 3D culture were monitored by fluorescent and confocal microscopy upon calcein-AM/propidium iodide (CAM/PI) staining every seven days. The glioblastoma 3D model was validated using temozolomide (TMZ) treatments 3 days in a row with a recovery period. Cell viability by MTT and resistance-related gene expression (MGMT and ABCB1) by qPCR were assessed after 28 days. The same TMZ treatment schedule was applied in 2D U87 cell culture for comparison purposes. Results: Within a long-term 3D model system in alginate fibers, U87 cells remained viable for up to 28 days. On day 7, cells formed visible aggregates oriented to the microfiber periphery. TMZ treatment reduced cell growth but increased drug resistance-related gene expression. The latter effect was more pronounced in 3D compared to 2D cell culture. Conclusion: Herein, we described a long-term glioblastoma 3D model system that could be particularly helpful for drug testing and treatment optimization.
PB  - Basel : MDPI
T2  - Brain Sciences
T1  - Development and validation of a long-term 3D glioblastoma cell culture in alginate microfibers as a novel bio-mimicking model system for preclinical drug testing
IS  - 8
VL  - 11
DO  - 10.3390/brainsci11081025
SP  - 1025
ER  - 

@article{
author = "Dragoj, Miodrag and Stojkovska, Jasmina and Stanković, Tijana and Dinić, Jelena and Podolski-Renić, Ana and Obradović, Bojana and Pešić, Milica",
year = "2021",
abstract = "Background: Various three-dimensional (3D) glioblastoma cell culture models have a limited duration of viability. Our aim was to develop a long-term 3D glioblastoma model, which is necessary for reliable drug response studies. Methods: Human U87 glioblastoma cells were cultured in alginate microfibers for 28 days. Cell growth, viability, morphology, and aggregation in 3D culture were monitored by fluorescent and confocal microscopy upon calcein-AM/propidium iodide (CAM/PI) staining every seven days. The glioblastoma 3D model was validated using temozolomide (TMZ) treatments 3 days in a row with a recovery period. Cell viability by MTT and resistance-related gene expression (MGMT and ABCB1) by qPCR were assessed after 28 days. The same TMZ treatment schedule was applied in 2D U87 cell culture for comparison purposes. Results: Within a long-term 3D model system in alginate fibers, U87 cells remained viable for up to 28 days. On day 7, cells formed visible aggregates oriented to the microfiber periphery. TMZ treatment reduced cell growth but increased drug resistance-related gene expression. The latter effect was more pronounced in 3D compared to 2D cell culture. Conclusion: Herein, we described a long-term glioblastoma 3D model system that could be particularly helpful for drug testing and treatment optimization.",
publisher = "Basel : MDPI",
journal = "Brain Sciences",
title = "Development and validation of a long-term 3D glioblastoma cell culture in alginate microfibers as a novel bio-mimicking model system for preclinical drug testing",
number = "8",
volume = "11",
doi = "10.3390/brainsci11081025",
pages = "1025"
}

Dragoj, M., Stojkovska, J., Stanković, T., Dinić, J., Podolski-Renić, A., Obradović, B.,& Pešić, M.. (2021). Development and validation of a long-term 3D glioblastoma cell culture in alginate microfibers as a novel bio-mimicking model system for preclinical drug testing. in Brain Sciences
Basel : MDPI., 11(8), 1025.
https://doi.org/10.3390/brainsci11081025

Dragoj M, Stojkovska J, Stanković T, Dinić J, Podolski-Renić A, Obradović B, Pešić M. Development and validation of a long-term 3D glioblastoma cell culture in alginate microfibers as a novel bio-mimicking model system for preclinical drug testing. in Brain Sciences. 2021;11(8):1025.
doi:10.3390/brainsci11081025 .

Dragoj, Miodrag, Stojkovska, Jasmina, Stanković, Tijana, Dinić, Jelena, Podolski-Renić, Ana, Obradović, Bojana, Pešić, Milica, "Development and validation of a long-term 3D glioblastoma cell culture in alginate microfibers as a novel bio-mimicking model system for preclinical drug testing" in Brain Sciences, 11, no. 8 (2021):1025,
https://doi.org/10.3390/brainsci11081025 . .

TY  - JOUR
AU  - Podolski-Renić, Ana
AU  - Dinić, Jelena
AU  - Stanković, Tijana
AU  - Tsakovska, Ivanka
AU  - Pajeva, Ilza
AU  - Tuccinardi, Tiziano
AU  - Botta, Lorenzo
AU  - Schenone, Silvia
AU  - Pešić, Milica
PY  - 2021
UR  - https://www.mdpi.com/2072-6694/13/21/5308
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4631
AB  - Tyrosine kinase inhibitors (TKIs) often interact with the multidrug resistant (MDR) phenotype of cancer cells. In some cases, TKIs increase the susceptibility of MDR cancer cells to chemotherapy. As the overexpression of membrane transporter P‐glycoprotein (P‐gp) is the most com-mon alteration in MDR cancer cells, we investigated the effects of TKI pyrazolo[3,4‐d]pyrimidines on P‐gp inhibition in two cellular models comprising sensitive and corresponding MDR cancer cells (human non‐small cell lung carcinoma and colorectal adenocarcinoma). Tested TKIs showed collateral sensitivity by inducing stronger inhibition of MDR cancer cell line viability. Moreover, TKIs directly interacted with P‐gp and inhibited its ATPase activity. Their potential P‐gp binding site was proposed by molecular docking simulations. TKIs reversed resistance to doxorubicin and paclitaxel in a concentration‐dependent manner. The expression studies excluded the indirect effect of TKIs on P‐gp through regulation of its expression. A kinetics study showed that TKIs decreased P‐gp activity and this effect was sustained for seven days in both MDR models. Therefore, pyrazolo[3,4‐d]pyrimidines with potential for reversing P‐gp‐mediated MDR even in prolonged treatments can be considered a new therapeutic strategy for overcoming cancer MDR.
PB  - Basel: MDPI
T2  - Cancers
T1  - New therapeutic strategy for overcoming multidrug resistance in cancer cells with pyrazolo[3,4‐d]pyrimidine tyrosine kinase inhibitors
IS  - 21
VL  - 13
DO  - 10.3390/cancers13215308
SP  - 5308
ER  - 

@article{
author = "Podolski-Renić, Ana and Dinić, Jelena and Stanković, Tijana and Tsakovska, Ivanka and Pajeva, Ilza and Tuccinardi, Tiziano and Botta, Lorenzo and Schenone, Silvia and Pešić, Milica",
year = "2021",
abstract = "Tyrosine kinase inhibitors (TKIs) often interact with the multidrug resistant (MDR) phenotype of cancer cells. In some cases, TKIs increase the susceptibility of MDR cancer cells to chemotherapy. As the overexpression of membrane transporter P‐glycoprotein (P‐gp) is the most com-mon alteration in MDR cancer cells, we investigated the effects of TKI pyrazolo[3,4‐d]pyrimidines on P‐gp inhibition in two cellular models comprising sensitive and corresponding MDR cancer cells (human non‐small cell lung carcinoma and colorectal adenocarcinoma). Tested TKIs showed collateral sensitivity by inducing stronger inhibition of MDR cancer cell line viability. Moreover, TKIs directly interacted with P‐gp and inhibited its ATPase activity. Their potential P‐gp binding site was proposed by molecular docking simulations. TKIs reversed resistance to doxorubicin and paclitaxel in a concentration‐dependent manner. The expression studies excluded the indirect effect of TKIs on P‐gp through regulation of its expression. A kinetics study showed that TKIs decreased P‐gp activity and this effect was sustained for seven days in both MDR models. Therefore, pyrazolo[3,4‐d]pyrimidines with potential for reversing P‐gp‐mediated MDR even in prolonged treatments can be considered a new therapeutic strategy for overcoming cancer MDR.",
publisher = "Basel: MDPI",
journal = "Cancers",
title = "New therapeutic strategy for overcoming multidrug resistance in cancer cells with pyrazolo[3,4‐d]pyrimidine tyrosine kinase inhibitors",
number = "21",
volume = "13",
doi = "10.3390/cancers13215308",
pages = "5308"
}

Podolski-Renić, A., Dinić, J., Stanković, T., Tsakovska, I., Pajeva, I., Tuccinardi, T., Botta, L., Schenone, S.,& Pešić, M.. (2021). New therapeutic strategy for overcoming multidrug resistance in cancer cells with pyrazolo[3,4‐d]pyrimidine tyrosine kinase inhibitors. in Cancers
Basel: MDPI., 13(21), 5308.
https://doi.org/10.3390/cancers13215308

Podolski-Renić A, Dinić J, Stanković T, Tsakovska I, Pajeva I, Tuccinardi T, Botta L, Schenone S, Pešić M. New therapeutic strategy for overcoming multidrug resistance in cancer cells with pyrazolo[3,4‐d]pyrimidine tyrosine kinase inhibitors. in Cancers. 2021;13(21):5308.
doi:10.3390/cancers13215308 .

Podolski-Renić, Ana, Dinić, Jelena, Stanković, Tijana, Tsakovska, Ivanka, Pajeva, Ilza, Tuccinardi, Tiziano, Botta, Lorenzo, Schenone, Silvia, Pešić, Milica, "New therapeutic strategy for overcoming multidrug resistance in cancer cells with pyrazolo[3,4‐d]pyrimidine tyrosine kinase inhibitors" in Cancers, 13, no. 21 (2021):5308,
https://doi.org/10.3390/cancers13215308 . .

TY  - JOUR
AU  - Andrei, Luca
AU  - Kasas, Sandor
AU  - Ochoa Garrido, Ignacio
AU  - Stanković, Tijana
AU  - Suárez Korsnes, Mónica
AU  - Vaclavikova, Radka
AU  - Assaraf, Yehuda G.
AU  - Pešić, Milica
PY  - 2020
UR  - https://www.sciencedirect.com/science/article/pii/S136876461930055X?via%3Dihub
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3508
AB  - The complexity of cancer biology and its clinical manifestation are driven by genetic, epigenetic, transcriptomic, proteomic and metabolomic alterations, supported by genomic instability as well as by environmental conditions and lifestyle factors. Although novel therapeutic modalities are being introduced, efficacious cancer therapy is not achieved due to the frequent emergence of distinct mechanisms of multidrug resistance (MDR). Advanced technologies with the potential to identify and characterize cancer MDR could aid in selecting the most efficacious therapeutic regimens and prevent inappropriate treatments of cancer patients. Herein, we aim to present technological tools that will enhance our ability to surmount drug resistance in cancer in the upcoming decade. Some of these tools are already in practice such as next-generation sequencing. Identification of genes and different types of RNAs contributing to the MDR phenotype, as well as their molecular targets, are of paramount importance for the development of new therapeutic strategies aimed to enhance drug response in resistant tumors. Other techniques known for many decades are in the process of adaptation and improvement to study cancer cells' characteristics and biological behavior including atomic force microscopy (AFM) and live-cell imaging. AFM can monitor in real-time single molecules or molecular complexes as well as structural alterations occurring in cancer cells induced upon treatment with various antitumor agents. Cell tracking methodologies and software tools recently progressed towards quantitative analysis of the spatio-temporal dynamics of heterogeneous cancer cell populations and enabled direct monitoring of cells and their descendants in 3D cultures. Besides, novel 3D systems with the advanced mimicking of the in vivo tumor microenvironment are applicable to study different cancer biology phenotypes, particularly drug-resistant and aggressive ones. They are also suitable for investigating new anticancer treatment modalities. The ultimate goal of using phenotype-driven 3D cultures for the investigation of patient biopsies as the most appropriate in vivo mimicking model, can be achieved in the near future.
T2  - Drug Resistance Updates
T1  - Advanced technological tools to study multidrug resistance in cancer.
VL  - 48
DO  - 10.1016/j.drup.2019.100658
SP  - 100658
ER  - 

@article{
author = "Andrei, Luca and Kasas, Sandor and Ochoa Garrido, Ignacio and Stanković, Tijana and Suárez Korsnes, Mónica and Vaclavikova, Radka and Assaraf, Yehuda G. and Pešić, Milica",
year = "2020",
abstract = "The complexity of cancer biology and its clinical manifestation are driven by genetic, epigenetic, transcriptomic, proteomic and metabolomic alterations, supported by genomic instability as well as by environmental conditions and lifestyle factors. Although novel therapeutic modalities are being introduced, efficacious cancer therapy is not achieved due to the frequent emergence of distinct mechanisms of multidrug resistance (MDR). Advanced technologies with the potential to identify and characterize cancer MDR could aid in selecting the most efficacious therapeutic regimens and prevent inappropriate treatments of cancer patients. Herein, we aim to present technological tools that will enhance our ability to surmount drug resistance in cancer in the upcoming decade. Some of these tools are already in practice such as next-generation sequencing. Identification of genes and different types of RNAs contributing to the MDR phenotype, as well as their molecular targets, are of paramount importance for the development of new therapeutic strategies aimed to enhance drug response in resistant tumors. Other techniques known for many decades are in the process of adaptation and improvement to study cancer cells' characteristics and biological behavior including atomic force microscopy (AFM) and live-cell imaging. AFM can monitor in real-time single molecules or molecular complexes as well as structural alterations occurring in cancer cells induced upon treatment with various antitumor agents. Cell tracking methodologies and software tools recently progressed towards quantitative analysis of the spatio-temporal dynamics of heterogeneous cancer cell populations and enabled direct monitoring of cells and their descendants in 3D cultures. Besides, novel 3D systems with the advanced mimicking of the in vivo tumor microenvironment are applicable to study different cancer biology phenotypes, particularly drug-resistant and aggressive ones. They are also suitable for investigating new anticancer treatment modalities. The ultimate goal of using phenotype-driven 3D cultures for the investigation of patient biopsies as the most appropriate in vivo mimicking model, can be achieved in the near future.",
journal = "Drug Resistance Updates",
title = "Advanced technological tools to study multidrug resistance in cancer.",
volume = "48",
doi = "10.1016/j.drup.2019.100658",
pages = "100658"
}

Andrei, L., Kasas, S., Ochoa Garrido, I., Stanković, T., Suárez Korsnes, M., Vaclavikova, R., Assaraf, Y. G.,& Pešić, M.. (2020). Advanced technological tools to study multidrug resistance in cancer.. in Drug Resistance Updates, 48, 100658.
https://doi.org/10.1016/j.drup.2019.100658

Andrei L, Kasas S, Ochoa Garrido I, Stanković T, Suárez Korsnes M, Vaclavikova R, Assaraf YG, Pešić M. Advanced technological tools to study multidrug resistance in cancer.. in Drug Resistance Updates. 2020;48:100658.
doi:10.1016/j.drup.2019.100658 .

Andrei, Luca, Kasas, Sandor, Ochoa Garrido, Ignacio, Stanković, Tijana, Suárez Korsnes, Mónica, Vaclavikova, Radka, Assaraf, Yehuda G., Pešić, Milica, "Advanced technological tools to study multidrug resistance in cancer." in Drug Resistance Updates, 48 (2020):100658,
https://doi.org/10.1016/j.drup.2019.100658 . .

TY  - CONF
AU  - Stanković, Tijana
AU  - Dragoj, Miodrag
AU  - Stojkovska, J
AU  - Dinić, Jelena
AU  - Podolski-Renić, Ana
AU  - Obradović, B.
AU  - Pešić, Milica
PY  - 2020
UR  - https://www.eaa2020.org/abstracts
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4109
AB  - Introduction
Various three dimensional (3D) biomimicking human glioblastoma cell culture
models have been developed in the last decade. However, all these models have
limited duration of viable cell cultures, which is necessary for reliable drug response
studies. Therefore, we are developing a novel long-term 3D glioblastoma
biomimicking model system that would enable optimal drug testing at clinically
relevant duration.
Material and Methods
3D culture of human U87 glioblastoma cells in alginate microfibers was followed for
28 days under static and dynamic conditions. To characterize this culture, cell
growth and viability were assessed by trypan blue dye exclusion test every seven
days, until 28th day. At the same time points, cell morphology and aggregation
were analyzed by fluorescent and confocal microscopy upon calcein-AM/propidium
iodide staining. Drug testing was validated by comparing effects of two different
TMZ treatment modalities on cell viability, morphology, aggregation and resistancerelated
gene expression (MGMT and ABCB1). Specifically, effects of 3 treatments
with 100 μM TMZ, starting from day 7 (X=7), were compared between subsequent
treatment modality (day by day treatments, X+1) and protractive treatment
modality (every 7 day, X+7).
Results and Discussions
Within the newly established static 3D model system, U87 glioblastoma cells
remained viable up to 28 days. The number of cells increased over time, while the
cell death rate was low. At day 7, cells formed visible aggregates oriented to
microfiber periphery, towards the source of oxygen and nutrients. Importantly, both TMZ treatment modalities had the same effect on cell viability in the static longterm
3D culture. However, protractive treatment reduced the expression of MGMT
and ABCB1observed with subsequent treatments.
Further work will be focused on the development of dynamic long-term 3D cell
culture in perfusion bioreactor. In this advanced model system, U87 cells in alginate
microfibers will be exposed to continuous media flow for 28 days. Introduction of
media flow, as the tumor microenvironment factor, may promote different
glioblastoma phenotype making it more reliable in vitro model for drug testing.
Conclusion
Based on the results obtained so far, we can conclude that our model system could
be suitable for drug testing in glioblastoma gaining relevant results for future
clinical studies.
PB  - European Association for Cancer Research
C3  - EACR-AACR-ASPIC Basic and Translational Research Conference "Tumor Microenvironment"; 2020 Mar 02-04;Lisbon, Portugal
T1  - Validation of long-term 3D glioblastoma cell culture as a novel biomimicking model system for preclinical drug testing
SP  - P-303
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_4109
ER  - 

@conference{
author = "Stanković, Tijana and Dragoj, Miodrag and Stojkovska, J and Dinić, Jelena and Podolski-Renić, Ana and Obradović, B. and Pešić, Milica",
year = "2020",
abstract = "Introduction
Various three dimensional (3D) biomimicking human glioblastoma cell culture
models have been developed in the last decade. However, all these models have
limited duration of viable cell cultures, which is necessary for reliable drug response
studies. Therefore, we are developing a novel long-term 3D glioblastoma
biomimicking model system that would enable optimal drug testing at clinically
relevant duration.
Material and Methods
3D culture of human U87 glioblastoma cells in alginate microfibers was followed for
28 days under static and dynamic conditions. To characterize this culture, cell
growth and viability were assessed by trypan blue dye exclusion test every seven
days, until 28th day. At the same time points, cell morphology and aggregation
were analyzed by fluorescent and confocal microscopy upon calcein-AM/propidium
iodide staining. Drug testing was validated by comparing effects of two different
TMZ treatment modalities on cell viability, morphology, aggregation and resistancerelated
gene expression (MGMT and ABCB1). Specifically, effects of 3 treatments
with 100 μM TMZ, starting from day 7 (X=7), were compared between subsequent
treatment modality (day by day treatments, X+1) and protractive treatment
modality (every 7 day, X+7).
Results and Discussions
Within the newly established static 3D model system, U87 glioblastoma cells
remained viable up to 28 days. The number of cells increased over time, while the
cell death rate was low. At day 7, cells formed visible aggregates oriented to
microfiber periphery, towards the source of oxygen and nutrients. Importantly, both TMZ treatment modalities had the same effect on cell viability in the static longterm
3D culture. However, protractive treatment reduced the expression of MGMT
and ABCB1observed with subsequent treatments.
Further work will be focused on the development of dynamic long-term 3D cell
culture in perfusion bioreactor. In this advanced model system, U87 cells in alginate
microfibers will be exposed to continuous media flow for 28 days. Introduction of
media flow, as the tumor microenvironment factor, may promote different
glioblastoma phenotype making it more reliable in vitro model for drug testing.
Conclusion
Based on the results obtained so far, we can conclude that our model system could
be suitable for drug testing in glioblastoma gaining relevant results for future
clinical studies.",
publisher = "European Association for Cancer Research",
journal = "EACR-AACR-ASPIC Basic and Translational Research Conference "Tumor Microenvironment"; 2020 Mar 02-04;Lisbon, Portugal",
title = "Validation of long-term 3D glioblastoma cell culture as a novel biomimicking model system for preclinical drug testing",
pages = "P-303",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_4109"
}

Stanković, T., Dragoj, M., Stojkovska, J., Dinić, J., Podolski-Renić, A., Obradović, B.,& Pešić, M.. (2020). Validation of long-term 3D glioblastoma cell culture as a novel biomimicking model system for preclinical drug testing. in EACR-AACR-ASPIC Basic and Translational Research Conference "Tumor Microenvironment"; 2020 Mar 02-04;Lisbon, Portugal
European Association for Cancer Research., P-303.
https://hdl.handle.net/21.15107/rcub_ibiss_4109

Stanković T, Dragoj M, Stojkovska J, Dinić J, Podolski-Renić A, Obradović B, Pešić M. Validation of long-term 3D glioblastoma cell culture as a novel biomimicking model system for preclinical drug testing. in EACR-AACR-ASPIC Basic and Translational Research Conference "Tumor Microenvironment"; 2020 Mar 02-04;Lisbon, Portugal. 2020;:P-303.
https://hdl.handle.net/21.15107/rcub_ibiss_4109 .

Stanković, Tijana, Dragoj, Miodrag, Stojkovska, J, Dinić, Jelena, Podolski-Renić, Ana, Obradović, B., Pešić, Milica, "Validation of long-term 3D glioblastoma cell culture as a novel biomimicking model system for preclinical drug testing" in EACR-AACR-ASPIC Basic and Translational Research Conference "Tumor Microenvironment"; 2020 Mar 02-04;Lisbon, Portugal (2020):P-303,
https://hdl.handle.net/21.15107/rcub_ibiss_4109 .

TY  - CONF
AU  - Jovanović, Mirna
AU  - Podolski-Renić, Ana
AU  - Zhukovsky, Danill
AU  - Nešović, Marija
AU  - Dragoj, Miodrag
AU  - Stanković, Tijana
AU  - Dinić, Jelena
AU  - Zalubovskis, Raivis
AU  - Krasavin, Mikhail
AU  - Pešić, Milica
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6047
AB  - Introduction: Cancer cells have high expression of thioredoxin (Trx) system proteins - Tx and thioredoxin
reductase (TrxR) [1,2]. lnhibition of Trx system is a perspective target of chemotherapy development [3,4].
Here we describe biological effects of six new Ugi-Michael acceptors (UMAs), potential TrxR1 inhibitors, in
human neuroblastoma cell line (SH-SY5Y) and normal human keratinocytes (HaCaT).
Materials & Methods: lnhibitory potential of UMAs was assessed by TxR1 and insulin assay. Cytotoxicity
was determined by MTT assay. Flow cytometry was used to assess reactive oxygen and nitrogen species
(RONS) levels by DHE and DHR staining and to analyze cell death by AV/PI labeling.
Reults: TrxR1 and insulin assay proved that six novel UMAs are inhibitors of TrxR1 and Trx system. The
inhibitors of TrxR1 showed cytotoxic effect in both cell lines. However, UMAs evoked increase in RONS only in neuroblastoma cells, but not in keratinocytes. These compounds also induced necrotic cell death in both cell lines. lmportantly, cell death induction was more pronounced in SH-SY5Y cells and in accordance with observed elevation of RONS levels.
PB  - International society of Antioxidants
C3  - 21st lnternational Conference on Oxidative Stress Reduction, Redox Homeostasis and Antioxidants; 2019, Jun 20-21; Paris, France
T1  - Development of TrxR1 inhibitors yielded six new Ugi-Michael acceptors with anticancer effects in neuroblastoma cells
SP  - 102
EP  - 102
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6047
ER  - 

@conference{
author = "Jovanović, Mirna and Podolski-Renić, Ana and Zhukovsky, Danill and Nešović, Marija and Dragoj, Miodrag and Stanković, Tijana and Dinić, Jelena and Zalubovskis, Raivis and Krasavin, Mikhail and Pešić, Milica",
year = "2019",
abstract = "Introduction: Cancer cells have high expression of thioredoxin (Trx) system proteins - Tx and thioredoxin
reductase (TrxR) [1,2]. lnhibition of Trx system is a perspective target of chemotherapy development [3,4].
Here we describe biological effects of six new Ugi-Michael acceptors (UMAs), potential TrxR1 inhibitors, in
human neuroblastoma cell line (SH-SY5Y) and normal human keratinocytes (HaCaT).
Materials & Methods: lnhibitory potential of UMAs was assessed by TxR1 and insulin assay. Cytotoxicity
was determined by MTT assay. Flow cytometry was used to assess reactive oxygen and nitrogen species
(RONS) levels by DHE and DHR staining and to analyze cell death by AV/PI labeling.
Reults: TrxR1 and insulin assay proved that six novel UMAs are inhibitors of TrxR1 and Trx system. The
inhibitors of TrxR1 showed cytotoxic effect in both cell lines. However, UMAs evoked increase in RONS only in neuroblastoma cells, but not in keratinocytes. These compounds also induced necrotic cell death in both cell lines. lmportantly, cell death induction was more pronounced in SH-SY5Y cells and in accordance with observed elevation of RONS levels.",
publisher = "International society of Antioxidants",
journal = "21st lnternational Conference on Oxidative Stress Reduction, Redox Homeostasis and Antioxidants; 2019, Jun 20-21; Paris, France",
title = "Development of TrxR1 inhibitors yielded six new Ugi-Michael acceptors with anticancer effects in neuroblastoma cells",
pages = "102-102",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6047"
}

Jovanović, M., Podolski-Renić, A., Zhukovsky, D., Nešović, M., Dragoj, M., Stanković, T., Dinić, J., Zalubovskis, R., Krasavin, M.,& Pešić, M.. (2019). Development of TrxR1 inhibitors yielded six new Ugi-Michael acceptors with anticancer effects in neuroblastoma cells. in 21st lnternational Conference on Oxidative Stress Reduction, Redox Homeostasis and Antioxidants; 2019, Jun 20-21; Paris, France
International society of Antioxidants., 102-102.
https://hdl.handle.net/21.15107/rcub_ibiss_6047

Jovanović M, Podolski-Renić A, Zhukovsky D, Nešović M, Dragoj M, Stanković T, Dinić J, Zalubovskis R, Krasavin M, Pešić M. Development of TrxR1 inhibitors yielded six new Ugi-Michael acceptors with anticancer effects in neuroblastoma cells. in 21st lnternational Conference on Oxidative Stress Reduction, Redox Homeostasis and Antioxidants; 2019, Jun 20-21; Paris, France. 2019;:102-102.
https://hdl.handle.net/21.15107/rcub_ibiss_6047 .

Jovanović, Mirna, Podolski-Renić, Ana, Zhukovsky, Danill, Nešović, Marija, Dragoj, Miodrag, Stanković, Tijana, Dinić, Jelena, Zalubovskis, Raivis, Krasavin, Mikhail, Pešić, Milica, "Development of TrxR1 inhibitors yielded six new Ugi-Michael acceptors with anticancer effects in neuroblastoma cells" in 21st lnternational Conference on Oxidative Stress Reduction, Redox Homeostasis and Antioxidants; 2019, Jun 20-21; Paris, France (2019):102-102,
https://hdl.handle.net/21.15107/rcub_ibiss_6047 .

TY  - CONF
AU  - Nešović, Marija
AU  - Podolski-Renić, Ana
AU  - Stanković, Tijana
AU  - Divac Rankov, Aleksandra
AU  - Nikolić, Igor
AU  - Tasić, Goran
AU  - Botta, Maurizio
AU  - Pešić, Milica
AU  - Dinić, Jelena
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6048
AB  - Background: Glioblastoma multiforme (GBM) are the most frequent and aggressive (WHO
grade IV) brain tumors in adults. GBM have high expression of c-Src tyrosine kinase involved in
survival, migration and invasiveness of tumor cells. Thus, c-Src emerged as a potential target for
GBM therapy. Materials and methods: Antiproliferative effect of c-Src inhibitors pyrozolo[3,4-d]
pyrimidines, Si306 and its prodrug pro-Si306, was assessed in human GBM cell line U87, multidrug
resistant (MDR) U87-TxR, and primary GBM cells by MTT assay. Anti-migratory and anti-invasive
effects of c-Src inhibitors were evaluated by gelatin degradation and transwell invasion assays.
Their effect on c-Src, extracellular signal-related kinase (ERK), and focal adhesion kinase (FAK)
expression was analyzed by western-blot and flow-cytometry. Zebrafish model was used to
evaluate anti-invasive potential of pro-Si306 in U87 xenografts in vivo. Results and conclusions:
c-Src inhibitors were more efficient in cell growth inhibition compared to dasatinib, a well-known tyrosine kinase inhibitor. The potency of Si306 and pro-Si306 was not affected by the
MDR phenotype. Migratory potential of U87, U87-TxR, and primary GBM cells was significantly
decreased by both inhibitors. Si306 and pro-Si306 also compromised cells’ ability to degrade the
matrix and invade through basement membrane. Both compounds reduced phosporylation of
c-Src, and its downstream signaling components, ERK and FAK, in GBM cell lines. In vivo, pro-Si306 showed anti-invasive effect against U87 xenografts in zebrafish model. Considering their
ability to suppress migration and invasion and overcome MDR, Si306 and pro-Si306 could be
considered in GBM treatment alone or in combination with other chemotherapeutics.
PB  - Belgrade: Serbian Association for Cancer Research
C3  - Abstract Book: 4th Congress of the Serbian Association for Cancer Research with International Participation SDIR-4: Bringing Science to Oncology Practice: Where is Serbia?; 2019 Oct 3-5; Belgrade, Serbia
T1  - c-Src inhibitors pyrozolo[3,4-d]pyrimidines, Si306 and pro-Si306, evade multidrug resistant phenotype and suppress invasion in glioblastoma
SP  - 46
EP  - 46
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6048
ER  - 

@conference{
author = "Nešović, Marija and Podolski-Renić, Ana and Stanković, Tijana and Divac Rankov, Aleksandra and Nikolić, Igor and Tasić, Goran and Botta, Maurizio and Pešić, Milica and Dinić, Jelena",
year = "2019",
abstract = "Background: Glioblastoma multiforme (GBM) are the most frequent and aggressive (WHO
grade IV) brain tumors in adults. GBM have high expression of c-Src tyrosine kinase involved in
survival, migration and invasiveness of tumor cells. Thus, c-Src emerged as a potential target for
GBM therapy. Materials and methods: Antiproliferative effect of c-Src inhibitors pyrozolo[3,4-d]
pyrimidines, Si306 and its prodrug pro-Si306, was assessed in human GBM cell line U87, multidrug
resistant (MDR) U87-TxR, and primary GBM cells by MTT assay. Anti-migratory and anti-invasive
effects of c-Src inhibitors were evaluated by gelatin degradation and transwell invasion assays.
Their effect on c-Src, extracellular signal-related kinase (ERK), and focal adhesion kinase (FAK)
expression was analyzed by western-blot and flow-cytometry. Zebrafish model was used to
evaluate anti-invasive potential of pro-Si306 in U87 xenografts in vivo. Results and conclusions:
c-Src inhibitors were more efficient in cell growth inhibition compared to dasatinib, a well-known tyrosine kinase inhibitor. The potency of Si306 and pro-Si306 was not affected by the
MDR phenotype. Migratory potential of U87, U87-TxR, and primary GBM cells was significantly
decreased by both inhibitors. Si306 and pro-Si306 also compromised cells’ ability to degrade the
matrix and invade through basement membrane. Both compounds reduced phosporylation of
c-Src, and its downstream signaling components, ERK and FAK, in GBM cell lines. In vivo, pro-Si306 showed anti-invasive effect against U87 xenografts in zebrafish model. Considering their
ability to suppress migration and invasion and overcome MDR, Si306 and pro-Si306 could be
considered in GBM treatment alone or in combination with other chemotherapeutics.",
publisher = "Belgrade: Serbian Association for Cancer Research",
journal = "Abstract Book: 4th Congress of the Serbian Association for Cancer Research with International Participation SDIR-4: Bringing Science to Oncology Practice: Where is Serbia?; 2019 Oct 3-5; Belgrade, Serbia",
title = "c-Src inhibitors pyrozolo[3,4-d]pyrimidines, Si306 and pro-Si306, evade multidrug resistant phenotype and suppress invasion in glioblastoma",
pages = "46-46",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6048"
}

Nešović, M., Podolski-Renić, A., Stanković, T., Divac Rankov, A., Nikolić, I., Tasić, G., Botta, M., Pešić, M.,& Dinić, J.. (2019). c-Src inhibitors pyrozolo[3,4-d]pyrimidines, Si306 and pro-Si306, evade multidrug resistant phenotype and suppress invasion in glioblastoma. in Abstract Book: 4th Congress of the Serbian Association for Cancer Research with International Participation SDIR-4: Bringing Science to Oncology Practice: Where is Serbia?; 2019 Oct 3-5; Belgrade, Serbia
Belgrade: Serbian Association for Cancer Research., 46-46.
https://hdl.handle.net/21.15107/rcub_ibiss_6048

Nešović M, Podolski-Renić A, Stanković T, Divac Rankov A, Nikolić I, Tasić G, Botta M, Pešić M, Dinić J. c-Src inhibitors pyrozolo[3,4-d]pyrimidines, Si306 and pro-Si306, evade multidrug resistant phenotype and suppress invasion in glioblastoma. in Abstract Book: 4th Congress of the Serbian Association for Cancer Research with International Participation SDIR-4: Bringing Science to Oncology Practice: Where is Serbia?; 2019 Oct 3-5; Belgrade, Serbia. 2019;:46-46.
https://hdl.handle.net/21.15107/rcub_ibiss_6048 .

Nešović, Marija, Podolski-Renić, Ana, Stanković, Tijana, Divac Rankov, Aleksandra, Nikolić, Igor, Tasić, Goran, Botta, Maurizio, Pešić, Milica, Dinić, Jelena, "c-Src inhibitors pyrozolo[3,4-d]pyrimidines, Si306 and pro-Si306, evade multidrug resistant phenotype and suppress invasion in glioblastoma" in Abstract Book: 4th Congress of the Serbian Association for Cancer Research with International Participation SDIR-4: Bringing Science to Oncology Practice: Where is Serbia?; 2019 Oct 3-5; Belgrade, Serbia (2019):46-46,
https://hdl.handle.net/21.15107/rcub_ibiss_6048 .

TY  - CONF
AU  - Stojković Burić, Sonja
AU  - Podolski-Renić, Ana
AU  - Dinić, Jelena
AU  - Stanković, Tijana
AU  - Jovanović, Mirna
AU  - Hadžić, Stefan
AU  - Ayuso, Jose
AU  - Virumbrales-Muñoz, María
AU  - Fernández, Luis
AU  - Ochoa, Ignacio
AU  - Pérez-García, Victor
AU  - Pešić, Milica
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6043
AB  - Development of chemoresistance and the invasion of cancer cells into surrounding brain tissue are major obstacles to successful glioma treatment. New therapeutic approaches are warranted to improve the survival of glioma patients. The purpose of this study was to assess the potential of lipophilic antioxidant coenzyme Q10 (CoQ10) to increase sensitivity to temozolomide (TMZ) and suppress glioma cells invasion. Therefore, we have developed TMZ resistant RC6 rat glioma cell line with altered antioxidant capacity and high invasion potential. CoQ10 in combination with TMZ exerted a synergistic effect additionally confirmed in a 3D model of microfluidic devices. Co-treatment with TMZ increased
expression of mitochondrial antioxidant enzymes in RC6 cells. The anti-invasive potential was studied by gelatin degradation and 3D spheroid invasion assays. Inhibition of MMP9 gene expression as well as decreased N-cadherin and vimentin protein expression implied that CoQ10 can suppress invasiveness and the epithelial to mesenchymal transition in RC6 cells. Therefore, CoQ10 supplementation could be used with standard glioma treatment due to its potential to inhibit cancer cells invasion through modulation of the antioxidant capacity.
PB  - COST Action CA17104
C3  - Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug-resistant tumours: First Working-Group Meeting WG1 - WG4; 2019 Jan 30-31; Turin, Italy
T1  - The role of antioxidant, coenzyme Q10, in suppressing invasion of temozolomide resistant rat glioma
SP  - 32
EP  - 32
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6043
ER  - 

@conference{
author = "Stojković Burić, Sonja and Podolski-Renić, Ana and Dinić, Jelena and Stanković, Tijana and Jovanović, Mirna and Hadžić, Stefan and Ayuso, Jose and Virumbrales-Muñoz, María and Fernández, Luis and Ochoa, Ignacio and Pérez-García, Victor and Pešić, Milica",
year = "2019",
abstract = "Development of chemoresistance and the invasion of cancer cells into surrounding brain tissue are major obstacles to successful glioma treatment. New therapeutic approaches are warranted to improve the survival of glioma patients. The purpose of this study was to assess the potential of lipophilic antioxidant coenzyme Q10 (CoQ10) to increase sensitivity to temozolomide (TMZ) and suppress glioma cells invasion. Therefore, we have developed TMZ resistant RC6 rat glioma cell line with altered antioxidant capacity and high invasion potential. CoQ10 in combination with TMZ exerted a synergistic effect additionally confirmed in a 3D model of microfluidic devices. Co-treatment with TMZ increased
expression of mitochondrial antioxidant enzymes in RC6 cells. The anti-invasive potential was studied by gelatin degradation and 3D spheroid invasion assays. Inhibition of MMP9 gene expression as well as decreased N-cadherin and vimentin protein expression implied that CoQ10 can suppress invasiveness and the epithelial to mesenchymal transition in RC6 cells. Therefore, CoQ10 supplementation could be used with standard glioma treatment due to its potential to inhibit cancer cells invasion through modulation of the antioxidant capacity.",
publisher = "COST Action CA17104",
journal = "Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug-resistant tumours: First Working-Group Meeting WG1 - WG4; 2019 Jan 30-31; Turin, Italy",
title = "The role of antioxidant, coenzyme Q10, in suppressing invasion of temozolomide resistant rat glioma",
pages = "32-32",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6043"
}

Stojković Burić, S., Podolski-Renić, A., Dinić, J., Stanković, T., Jovanović, M., Hadžić, S., Ayuso, J., Virumbrales-Muñoz, M., Fernández, L., Ochoa, I., Pérez-García, V.,& Pešić, M.. (2019). The role of antioxidant, coenzyme Q10, in suppressing invasion of temozolomide resistant rat glioma. in Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug-resistant tumours: First Working-Group Meeting WG1 - WG4; 2019 Jan 30-31; Turin, Italy
COST Action CA17104., 32-32.
https://hdl.handle.net/21.15107/rcub_ibiss_6043

Stojković Burić S, Podolski-Renić A, Dinić J, Stanković T, Jovanović M, Hadžić S, Ayuso J, Virumbrales-Muñoz M, Fernández L, Ochoa I, Pérez-García V, Pešić M. The role of antioxidant, coenzyme Q10, in suppressing invasion of temozolomide resistant rat glioma. in Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug-resistant tumours: First Working-Group Meeting WG1 - WG4; 2019 Jan 30-31; Turin, Italy. 2019;:32-32.
https://hdl.handle.net/21.15107/rcub_ibiss_6043 .

Stojković Burić, Sonja, Podolski-Renić, Ana, Dinić, Jelena, Stanković, Tijana, Jovanović, Mirna, Hadžić, Stefan, Ayuso, Jose, Virumbrales-Muñoz, María, Fernández, Luis, Ochoa, Ignacio, Pérez-García, Victor, Pešić, Milica, "The role of antioxidant, coenzyme Q10, in suppressing invasion of temozolomide resistant rat glioma" in Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug-resistant tumours: First Working-Group Meeting WG1 - WG4; 2019 Jan 30-31; Turin, Italy (2019):32-32,
https://hdl.handle.net/21.15107/rcub_ibiss_6043 .

TY  - CONF
AU  - Dinić, Jelena
AU  - Nešović, Marija
AU  - Divac Rankov, Aleksandra
AU  - Podolski-Renić, Ana
AU  - Stanković, Tijana
AU  - Dragoj, Miodrag
AU  - Jovanović, Mirna
AU  - Lazić, Katarina
AU  - Dimas, Kostas
AU  - Botta, Maurizio
AU  - Pešić, Milica
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6042
AB  - Zebrafish (Danio rerio) is an excellent model for studying toxicity and biological activities of novel compounds with anticancer potential. This model is widely utilized in biological research as it is comparable to human counterpart both molecularly and pathologically. As an in vivo system for toxicology, zebrafish has numerous advantages such as rapid and ex utero development, transparent embryos in early stages, high fecundity allowing high-throughput screening and cost effectiveness. Furthermore, evaluation of known toxic compounds in zebrafish revealed 63–100% predictability making zebrafish a very useful tool for studying toxic effects [1, 2]. In addition, embryonic zebrafish cancer models can be used for studying pathways and processes relevant to human malignancy including tumor-induced angiogenesis, tumor invasiveness, proliferation and migration. These models can be generated using transgenesis, gene inactivation, xenotransplantation, and cancerogenic induction. Herein, we present the results obtained in zebrafish toxicity studies of siramesine, a sigma receptor agonist with anticancer potential. Concentration dependent increase in lethality, induced by siramesine treatment, was observed in zebrafish embryos at 24 h post fertilization (hpf), 48 hpf and 72 hpf. Various concentration dependent toxic effects on embryo development were also observed, as well as decreased hatching rate in embryos treated with 5 µM and 10 µM siramesine at 72 hpf. Results obtained in zebrafish cancer model generated via xenotransplantation are also presented. This model was utilized to study the effect of Src tyrosine kinase inhibitor pro-LDS10 on the invasiveness of microinjected human glioblastoma cell line U87. Treatment with 5 µM pro-LDS10 resulted in significant reduction of U87 migratory potential at 4 days post injection.
PB  - COST Action CA17104
C3  - Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug-resistant tumours: First Working-Group Meeting WG1 - WG4; 2019 Jan 30-31; Turin, Italy
T1  - Evaluation of anticancer compounds activity and toxicity in zebrafish model
SP  - 34
EP  - 34
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6042
ER  - 

@conference{
author = "Dinić, Jelena and Nešović, Marija and Divac Rankov, Aleksandra and Podolski-Renić, Ana and Stanković, Tijana and Dragoj, Miodrag and Jovanović, Mirna and Lazić, Katarina and Dimas, Kostas and Botta, Maurizio and Pešić, Milica",
year = "2019",
abstract = "Zebrafish (Danio rerio) is an excellent model for studying toxicity and biological activities of novel compounds with anticancer potential. This model is widely utilized in biological research as it is comparable to human counterpart both molecularly and pathologically. As an in vivo system for toxicology, zebrafish has numerous advantages such as rapid and ex utero development, transparent embryos in early stages, high fecundity allowing high-throughput screening and cost effectiveness. Furthermore, evaluation of known toxic compounds in zebrafish revealed 63–100% predictability making zebrafish a very useful tool for studying toxic effects [1, 2]. In addition, embryonic zebrafish cancer models can be used for studying pathways and processes relevant to human malignancy including tumor-induced angiogenesis, tumor invasiveness, proliferation and migration. These models can be generated using transgenesis, gene inactivation, xenotransplantation, and cancerogenic induction. Herein, we present the results obtained in zebrafish toxicity studies of siramesine, a sigma receptor agonist with anticancer potential. Concentration dependent increase in lethality, induced by siramesine treatment, was observed in zebrafish embryos at 24 h post fertilization (hpf), 48 hpf and 72 hpf. Various concentration dependent toxic effects on embryo development were also observed, as well as decreased hatching rate in embryos treated with 5 µM and 10 µM siramesine at 72 hpf. Results obtained in zebrafish cancer model generated via xenotransplantation are also presented. This model was utilized to study the effect of Src tyrosine kinase inhibitor pro-LDS10 on the invasiveness of microinjected human glioblastoma cell line U87. Treatment with 5 µM pro-LDS10 resulted in significant reduction of U87 migratory potential at 4 days post injection.",
publisher = "COST Action CA17104",
journal = "Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug-resistant tumours: First Working-Group Meeting WG1 - WG4; 2019 Jan 30-31; Turin, Italy",
title = "Evaluation of anticancer compounds activity and toxicity in zebrafish model",
pages = "34-34",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6042"
}

Dinić, J., Nešović, M., Divac Rankov, A., Podolski-Renić, A., Stanković, T., Dragoj, M., Jovanović, M., Lazić, K., Dimas, K., Botta, M.,& Pešić, M.. (2019). Evaluation of anticancer compounds activity and toxicity in zebrafish model. in Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug-resistant tumours: First Working-Group Meeting WG1 - WG4; 2019 Jan 30-31; Turin, Italy
COST Action CA17104., 34-34.
https://hdl.handle.net/21.15107/rcub_ibiss_6042

Dinić J, Nešović M, Divac Rankov A, Podolski-Renić A, Stanković T, Dragoj M, Jovanović M, Lazić K, Dimas K, Botta M, Pešić M. Evaluation of anticancer compounds activity and toxicity in zebrafish model. in Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug-resistant tumours: First Working-Group Meeting WG1 - WG4; 2019 Jan 30-31; Turin, Italy. 2019;:34-34.
https://hdl.handle.net/21.15107/rcub_ibiss_6042 .

Dinić, Jelena, Nešović, Marija, Divac Rankov, Aleksandra, Podolski-Renić, Ana, Stanković, Tijana, Dragoj, Miodrag, Jovanović, Mirna, Lazić, Katarina, Dimas, Kostas, Botta, Maurizio, Pešić, Milica, "Evaluation of anticancer compounds activity and toxicity in zebrafish model" in Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug-resistant tumours: First Working-Group Meeting WG1 - WG4; 2019 Jan 30-31; Turin, Italy (2019):34-34,
https://hdl.handle.net/21.15107/rcub_ibiss_6042 .

TY  - CONF
AU  - Dinić, Jelena
AU  - Podolski-Renić, Ana
AU  - Stanković, Tijana
AU  - Botta, Maurizio
AU  - Pešić, Milica
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6040
AB  - P-glycoprotein (P-gp) is an ATP-binding cassette (ABC) transporter whose
overexpression in cancer cells is one of the main causes of multidrug resistance (MDR).
P-gp overexpression is responsible for reduced intracellular accumulation and efficacy
of both targeted therapies and classic chemotherapeutics. Therefore, P-gp has an
important role in "absorption, distribution, metabolism, and excretion" – ADME
studies. It is also considered as the first cellular defense line and a part of so-called
“cellular immunity’. Tyrosine kinase inhibitors (TKIs) have been reported to interact
with ABC transporters, and in some cases increase the susceptibility of cancer cells to
chemotherapy. We have investigated the anticancer potential of novel tyrosine kinase
inhibitors pyrazolo[3,4-d] pyrimidines and their prodrugs against two pairs of sensitive
and MDR cancer cell lines with P-gp overexpression: non-small cell lung carcinoma
(NCI-H460 and NCI-H460/R) and colorectal carcinoma (DLD1 and DLD1-TxR). The
tested compounds displayed significant cell growth inhibition and enhanced the
efficacy of doxorubicin and paclitaxel in MDR cancer cells. Some of the TKIs directly
interacted with P-gp and inhibited its ATPase activity. A kinetics study showed that the
compounds increased the intracellular accumulation of the P-gp substrate rhodamine
123 in a time-dependent manner. Treatment with the compounds did not increase the
mRNA expression level of P-gp in resistant cancer cells. The investigated pyrazolo[3,4-
d] pyrimidines showed significant potential for reversing P-gp-mediated MDR even in
prolonged treatment, making them good candidates for further development regarding
treatment of resistant cancers.
PB  - Belgrade: Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade
C3  - Immunology at the Confluence of Multidisciplinary Approaches: abstract book: 2019 Dec 6-8; Belgrade, Serbia
T1  - Novel pyrazolo[3,4-d]pyrimidine derivatives supress P-glycoprotein activity and reverse multidrug resistance in cancer cells
SP  - 122
EP  - 122
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6040
ER  - 

@conference{
author = "Dinić, Jelena and Podolski-Renić, Ana and Stanković, Tijana and Botta, Maurizio and Pešić, Milica",
year = "2019",
abstract = "P-glycoprotein (P-gp) is an ATP-binding cassette (ABC) transporter whose
overexpression in cancer cells is one of the main causes of multidrug resistance (MDR).
P-gp overexpression is responsible for reduced intracellular accumulation and efficacy
of both targeted therapies and classic chemotherapeutics. Therefore, P-gp has an
important role in "absorption, distribution, metabolism, and excretion" – ADME
studies. It is also considered as the first cellular defense line and a part of so-called
“cellular immunity’. Tyrosine kinase inhibitors (TKIs) have been reported to interact
with ABC transporters, and in some cases increase the susceptibility of cancer cells to
chemotherapy. We have investigated the anticancer potential of novel tyrosine kinase
inhibitors pyrazolo[3,4-d] pyrimidines and their prodrugs against two pairs of sensitive
and MDR cancer cell lines with P-gp overexpression: non-small cell lung carcinoma
(NCI-H460 and NCI-H460/R) and colorectal carcinoma (DLD1 and DLD1-TxR). The
tested compounds displayed significant cell growth inhibition and enhanced the
efficacy of doxorubicin and paclitaxel in MDR cancer cells. Some of the TKIs directly
interacted with P-gp and inhibited its ATPase activity. A kinetics study showed that the
compounds increased the intracellular accumulation of the P-gp substrate rhodamine
123 in a time-dependent manner. Treatment with the compounds did not increase the
mRNA expression level of P-gp in resistant cancer cells. The investigated pyrazolo[3,4-
d] pyrimidines showed significant potential for reversing P-gp-mediated MDR even in
prolonged treatment, making them good candidates for further development regarding
treatment of resistant cancers.",
publisher = "Belgrade: Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade",
journal = "Immunology at the Confluence of Multidisciplinary Approaches: abstract book: 2019 Dec 6-8; Belgrade, Serbia",
title = "Novel pyrazolo[3,4-d]pyrimidine derivatives supress P-glycoprotein activity and reverse multidrug resistance in cancer cells",
pages = "122-122",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6040"
}

Dinić, J., Podolski-Renić, A., Stanković, T., Botta, M.,& Pešić, M.. (2019). Novel pyrazolo[3,4-d]pyrimidine derivatives supress P-glycoprotein activity and reverse multidrug resistance in cancer cells. in Immunology at the Confluence of Multidisciplinary Approaches: abstract book: 2019 Dec 6-8; Belgrade, Serbia
Belgrade: Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, University of Belgrade., 122-122.
https://hdl.handle.net/21.15107/rcub_ibiss_6040

Dinić J, Podolski-Renić A, Stanković T, Botta M, Pešić M. Novel pyrazolo[3,4-d]pyrimidine derivatives supress P-glycoprotein activity and reverse multidrug resistance in cancer cells. in Immunology at the Confluence of Multidisciplinary Approaches: abstract book: 2019 Dec 6-8; Belgrade, Serbia. 2019;:122-122.
https://hdl.handle.net/21.15107/rcub_ibiss_6040 .

Dinić, Jelena, Podolski-Renić, Ana, Stanković, Tijana, Botta, Maurizio, Pešić, Milica, "Novel pyrazolo[3,4-d]pyrimidine derivatives supress P-glycoprotein activity and reverse multidrug resistance in cancer cells" in Immunology at the Confluence of Multidisciplinary Approaches: abstract book: 2019 Dec 6-8; Belgrade, Serbia (2019):122-122,
https://hdl.handle.net/21.15107/rcub_ibiss_6040 .

TY  - CONF
AU  - Nešović, Marija
AU  - Milošević, Zorica
AU  - Banković, Jasna
AU  - Tsimplouli, Chrisiida
AU  - Sereti, Evangelia
AU  - Dragoj, Miodrag
AU  - Podolski-Renić, Ana
AU  - Stanković, Tijana
AU  - Jovanović, Mirna
AU  - Dimas, Kostantinos
AU  - Pešić, Milica
AU  - Dinić, Jelena
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6046
AB  - Resistance to chemotherapeutic agents represents a major issue in anticancer therapy.
Anaplastic thyroid carcinoma (ATC) has a poor prognosis due to its aggressive behavior and
resistance to treatment. Alterations in the PI3K/AKT/mTOR pathway and/or high expression
of ATP binding cassette transporters, such as P-glycoprotein and breast cancer resistance
protein (BCRP), are frequently linked to chemo-resistance. Autophagy is a key player in the
metabolic and therapeutic stress response and represents a potential target for anticancer
therapy. Autophagy induction in response to chemotherapeutics may contribute to both
drug efficacy as well as drug resistance. We assessed the therapeutic efficacy of dual mTOR
kinase inhibitor vistusertib (AZD2014) and paclitaxel (PTX) in combination in ATC cells. Rhocell line was generated from parental human thyroid carcinoma 8505C via the selection of cells with a low accumulation of rhodamine 123 (P-glycoprotein and BCRP substrate). Rhocells were 10-fold more resistant to PTX compared to 8505C cells and more tumorigenic. Both vistusertib and PTX induced autophagosome formation in the investigated cell lines. In combination, vistusertib sensitized Rho- cells to PTX via autophagy induction and proliferation inhibition, indicating a synergistic effect between the two compounds. Additionally, vistusertib and PTX combination in Rho- and 8505C cells inhibited cell migration
and invasion in vitro. Furthermore, vistusertib and PTX combination effectively suppressed
tumor growth of ATC xenografts in immunodeficient NSG mice in vivo. Considering chemoresistance and high invasive properties of ATC, described combined approach could be useful for the design of novel targeted treatment strategies in this malignancy
PB  - COST Action CA1513
C3  - Poster, Abstract Book: 3rd TRANSAutophagy CA15138 Annual Meeting 2019; 2019 Apr 23-25; Sofia, Bulgaria
T1  - Vistusertib (AZD2014), a dual mTOR kinase inhibitor, overcomes paclitaxel resistance in anaplastic thyroid carcinoma
SP  - 30
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6046
ER  - 

@conference{
author = "Nešović, Marija and Milošević, Zorica and Banković, Jasna and Tsimplouli, Chrisiida and Sereti, Evangelia and Dragoj, Miodrag and Podolski-Renić, Ana and Stanković, Tijana and Jovanović, Mirna and Dimas, Kostantinos and Pešić, Milica and Dinić, Jelena",
year = "2019",
abstract = "Resistance to chemotherapeutic agents represents a major issue in anticancer therapy.
Anaplastic thyroid carcinoma (ATC) has a poor prognosis due to its aggressive behavior and
resistance to treatment. Alterations in the PI3K/AKT/mTOR pathway and/or high expression
of ATP binding cassette transporters, such as P-glycoprotein and breast cancer resistance
protein (BCRP), are frequently linked to chemo-resistance. Autophagy is a key player in the
metabolic and therapeutic stress response and represents a potential target for anticancer
therapy. Autophagy induction in response to chemotherapeutics may contribute to both
drug efficacy as well as drug resistance. We assessed the therapeutic efficacy of dual mTOR
kinase inhibitor vistusertib (AZD2014) and paclitaxel (PTX) in combination in ATC cells. Rhocell line was generated from parental human thyroid carcinoma 8505C via the selection of cells with a low accumulation of rhodamine 123 (P-glycoprotein and BCRP substrate). Rhocells were 10-fold more resistant to PTX compared to 8505C cells and more tumorigenic. Both vistusertib and PTX induced autophagosome formation in the investigated cell lines. In combination, vistusertib sensitized Rho- cells to PTX via autophagy induction and proliferation inhibition, indicating a synergistic effect between the two compounds. Additionally, vistusertib and PTX combination in Rho- and 8505C cells inhibited cell migration
and invasion in vitro. Furthermore, vistusertib and PTX combination effectively suppressed
tumor growth of ATC xenografts in immunodeficient NSG mice in vivo. Considering chemoresistance and high invasive properties of ATC, described combined approach could be useful for the design of novel targeted treatment strategies in this malignancy",
publisher = "COST Action CA1513",
journal = "Poster, Abstract Book: 3rd TRANSAutophagy CA15138 Annual Meeting 2019; 2019 Apr 23-25; Sofia, Bulgaria",
title = "Vistusertib (AZD2014), a dual mTOR kinase inhibitor, overcomes paclitaxel resistance in anaplastic thyroid carcinoma",
pages = "30",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6046"
}

Nešović, M., Milošević, Z., Banković, J., Tsimplouli, C., Sereti, E., Dragoj, M., Podolski-Renić, A., Stanković, T., Jovanović, M., Dimas, K., Pešić, M.,& Dinić, J.. (2019). Vistusertib (AZD2014), a dual mTOR kinase inhibitor, overcomes paclitaxel resistance in anaplastic thyroid carcinoma. in Poster, Abstract Book: 3rd TRANSAutophagy CA15138 Annual Meeting 2019; 2019 Apr 23-25; Sofia, Bulgaria
COST Action CA1513., 30.
https://hdl.handle.net/21.15107/rcub_ibiss_6046

Nešović M, Milošević Z, Banković J, Tsimplouli C, Sereti E, Dragoj M, Podolski-Renić A, Stanković T, Jovanović M, Dimas K, Pešić M, Dinić J. Vistusertib (AZD2014), a dual mTOR kinase inhibitor, overcomes paclitaxel resistance in anaplastic thyroid carcinoma. in Poster, Abstract Book: 3rd TRANSAutophagy CA15138 Annual Meeting 2019; 2019 Apr 23-25; Sofia, Bulgaria. 2019;:30.
https://hdl.handle.net/21.15107/rcub_ibiss_6046 .

Nešović, Marija, Milošević, Zorica, Banković, Jasna, Tsimplouli, Chrisiida, Sereti, Evangelia, Dragoj, Miodrag, Podolski-Renić, Ana, Stanković, Tijana, Jovanović, Mirna, Dimas, Kostantinos, Pešić, Milica, Dinić, Jelena, "Vistusertib (AZD2014), a dual mTOR kinase inhibitor, overcomes paclitaxel resistance in anaplastic thyroid carcinoma" in Poster, Abstract Book: 3rd TRANSAutophagy CA15138 Annual Meeting 2019; 2019 Apr 23-25; Sofia, Bulgaria (2019):30,
https://hdl.handle.net/21.15107/rcub_ibiss_6046 .

TY  - CONF
AU  - Nešović, Marija
AU  - Podolski-Renić, Ana
AU  - Stanković, Tijana
AU  - Divac Rankov, Aleksandra
AU  - Fallacara, Anna Lucia
AU  - Schenone, Silvia
AU  - Botta, Maurizio
AU  - Pešić, Milica
AU  - Dinić, Jelena
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6045
AB  - Glioblastoma multiforme (GBM) are the most frequent and aggressive (WHO grade IV) brain
tumors in adults. GBM have high expression of c-Src tyrosine kinase involved in survival,
migration and invasiveness of tumor cells. Thus, c-Src emerged as a potential target for GBM
therapy. Cytotoxicity of c-Src inhibitors pyrozolo[3,4-d]pyrimidines, Si306 and its prodrug pro-Si306,
was investigated in human GBM cell line U87 and its multidrug resistant (MDR) counterpart
U87-TxR by MTT assay. Anti-migratory and anti-invasive effects of Si306 and pro-Si306 were
assessed by wound healing, gelatin degradation and transwell invasion assays. The effect of cSrc inhibitors on P-glycoprotein (P-gp) activity in U87-TxR cells was analyzed by flow cytometry. Their ability to reverse paclitaxel resistance in MDR cells was also assessed. Zebrafish model was used to evaluate anti-invasive potential of pro-Si306 on U87 xenografts in vivo. Novel c-Src inhibitors were significantly more efficient in cell growth inhibition compared to the well-known tyrosine kinase inhibitor dasatinib. The efficacy of Si306 and pro-Si306 was not affected by the MDR phenotype.
Migratory potential of U87 and U87-TxR cells was significantly decreased by both inhibitors.
The ability of cells to degrade the matrix and invade through basement membrane was also
significantly impaired upon treatment with Si306 and its prodrug. Assessment of intracellular
accumulation of fluorescent P-gp substrate showed that both compounds inhibited P-gp activity
in U87-TxR cells. Si306 and pro-Si306 also enhanced the paclitaxel efficacy in resistant
glioblastoma. In vivo pro-Si306 showed anti-invasive effect against U87 xenografts in zebrafish
model. Considering their ability to suppress migration and invasion and overcome MDR, Si306 and proSi306 could be considered in GBM treatment alone or in combination with other
chemotherapeutics.
PB  - COST Action CM1407
C3  - COST Action CM1407: Challenging organic syntheses inspired by naturefrom natural products chemistry to drug discovery: Meeting dedicated to Early career Investigators; 2019 Feb 18-19; Brussels, Belgium
T1  - The potential of c-Src inhibitors Si306 and pro-Si306 for suppressing invasion and overcoming multidrug resistance in glioblastoma
SP  - 9
EP  - 9
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6045
ER  - 

@conference{
author = "Nešović, Marija and Podolski-Renić, Ana and Stanković, Tijana and Divac Rankov, Aleksandra and Fallacara, Anna Lucia and Schenone, Silvia and Botta, Maurizio and Pešić, Milica and Dinić, Jelena",
year = "2019",
abstract = "Glioblastoma multiforme (GBM) are the most frequent and aggressive (WHO grade IV) brain
tumors in adults. GBM have high expression of c-Src tyrosine kinase involved in survival,
migration and invasiveness of tumor cells. Thus, c-Src emerged as a potential target for GBM
therapy. Cytotoxicity of c-Src inhibitors pyrozolo[3,4-d]pyrimidines, Si306 and its prodrug pro-Si306,
was investigated in human GBM cell line U87 and its multidrug resistant (MDR) counterpart
U87-TxR by MTT assay. Anti-migratory and anti-invasive effects of Si306 and pro-Si306 were
assessed by wound healing, gelatin degradation and transwell invasion assays. The effect of cSrc inhibitors on P-glycoprotein (P-gp) activity in U87-TxR cells was analyzed by flow cytometry. Their ability to reverse paclitaxel resistance in MDR cells was also assessed. Zebrafish model was used to evaluate anti-invasive potential of pro-Si306 on U87 xenografts in vivo. Novel c-Src inhibitors were significantly more efficient in cell growth inhibition compared to the well-known tyrosine kinase inhibitor dasatinib. The efficacy of Si306 and pro-Si306 was not affected by the MDR phenotype.
Migratory potential of U87 and U87-TxR cells was significantly decreased by both inhibitors.
The ability of cells to degrade the matrix and invade through basement membrane was also
significantly impaired upon treatment with Si306 and its prodrug. Assessment of intracellular
accumulation of fluorescent P-gp substrate showed that both compounds inhibited P-gp activity
in U87-TxR cells. Si306 and pro-Si306 also enhanced the paclitaxel efficacy in resistant
glioblastoma. In vivo pro-Si306 showed anti-invasive effect against U87 xenografts in zebrafish
model. Considering their ability to suppress migration and invasion and overcome MDR, Si306 and proSi306 could be considered in GBM treatment alone or in combination with other
chemotherapeutics.",
publisher = "COST Action CM1407",
journal = "COST Action CM1407: Challenging organic syntheses inspired by naturefrom natural products chemistry to drug discovery: Meeting dedicated to Early career Investigators; 2019 Feb 18-19; Brussels, Belgium",
title = "The potential of c-Src inhibitors Si306 and pro-Si306 for suppressing invasion and overcoming multidrug resistance in glioblastoma",
pages = "9-9",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6045"
}

Nešović, M., Podolski-Renić, A., Stanković, T., Divac Rankov, A., Fallacara, A. L., Schenone, S., Botta, M., Pešić, M.,& Dinić, J.. (2019). The potential of c-Src inhibitors Si306 and pro-Si306 for suppressing invasion and overcoming multidrug resistance in glioblastoma. in COST Action CM1407: Challenging organic syntheses inspired by naturefrom natural products chemistry to drug discovery: Meeting dedicated to Early career Investigators; 2019 Feb 18-19; Brussels, Belgium
COST Action CM1407., 9-9.
https://hdl.handle.net/21.15107/rcub_ibiss_6045

Nešović M, Podolski-Renić A, Stanković T, Divac Rankov A, Fallacara AL, Schenone S, Botta M, Pešić M, Dinić J. The potential of c-Src inhibitors Si306 and pro-Si306 for suppressing invasion and overcoming multidrug resistance in glioblastoma. in COST Action CM1407: Challenging organic syntheses inspired by naturefrom natural products chemistry to drug discovery: Meeting dedicated to Early career Investigators; 2019 Feb 18-19; Brussels, Belgium. 2019;:9-9.
https://hdl.handle.net/21.15107/rcub_ibiss_6045 .

Nešović, Marija, Podolski-Renić, Ana, Stanković, Tijana, Divac Rankov, Aleksandra, Fallacara, Anna Lucia, Schenone, Silvia, Botta, Maurizio, Pešić, Milica, Dinić, Jelena, "The potential of c-Src inhibitors Si306 and pro-Si306 for suppressing invasion and overcoming multidrug resistance in glioblastoma" in COST Action CM1407: Challenging organic syntheses inspired by naturefrom natural products chemistry to drug discovery: Meeting dedicated to Early career Investigators; 2019 Feb 18-19; Brussels, Belgium (2019):9-9,
https://hdl.handle.net/21.15107/rcub_ibiss_6045 .

TY  - JOUR
AU  - Stojković Burić, Sonja
AU  - Podolski-Renić, Ana
AU  - Dinić, Jelena
AU  - Stanković, Tijana
AU  - Jovanović, Mirna
AU  - Hadžić, Stefan
AU  - Ayuso, Jose M.
AU  - Virumbrales-Muñoz, María
AU  - Fernández, Luis J.
AU  - Ochoa, Ignacio
AU  - Pérez-García, Victor M.
AU  - Pešić, Milica
PY  - 2019
UR  - https://www.hindawi.com/journals/omcl/2019/3061607/
UR  - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC6432727
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3323
AB  - The main reasons for the inefficiency of standard glioblastoma (GBM) therapy are the occurrence of chemoresistance and the invasion of GBM cells into surrounding brain tissues. New therapeutic approaches obstructing these processes may provide substantial survival improvements. The purpose of this study was to assess the potential of lipophilic antioxidant coenzyme Q10 (CoQ10) as a scavenger of reactive oxygen species (ROS) to increase sensitivity to temozolomide (TMZ) and suppress glioma cell invasion. To that end, we used a previously established TMZ-resistant RC6 rat glioma cell line, characterized by increased production of ROS, altered antioxidative capacity, and high invasion potential. CoQ10 in combination with TMZ exerted a synergistic antiproliferative effect. These results were confirmed in a 3D model of microfluidic devices showing that the CoQ10 and TMZ combination is more cytotoxic to RC6 cells than TMZ monotherapy. In addition, cotreatment with TMZ increased expression of mitochondrial antioxidant enzymes in RC6 cells. The anti-invasive potential of the combined treatment was shown by gelatin degradation, Matrigel invasion, and 3D spheroid invasion assays as well as in animal models. Inhibition of MMP9 gene expression as well as decreased N-cadherin and vimentin protein expression implied that CoQ10 can suppress invasiveness and the epithelial to mesenchymal transition in RC6 cells. Therefore, our data provide evidences in favor of CoQ10 supplementation to standard GBM treatment due to its potential to inhibit GBM invasion through modulation of the antioxidant capacity.
T2  - Oxidative Medicine and Cellular Longevity
T1  - Modulation of Antioxidant Potential with Coenzyme Q10 Suppressed Invasion of Temozolomide-Resistant Rat Glioma In Vitro and In Vivo.
VL  - 2019
DO  - 10.1155/2019/3061607
SP  - 3061607
ER  - 

@article{
author = "Stojković Burić, Sonja and Podolski-Renić, Ana and Dinić, Jelena and Stanković, Tijana and Jovanović, Mirna and Hadžić, Stefan and Ayuso, Jose M. and Virumbrales-Muñoz, María and Fernández, Luis J. and Ochoa, Ignacio and Pérez-García, Victor M. and Pešić, Milica",
year = "2019",
abstract = "The main reasons for the inefficiency of standard glioblastoma (GBM) therapy are the occurrence of chemoresistance and the invasion of GBM cells into surrounding brain tissues. New therapeutic approaches obstructing these processes may provide substantial survival improvements. The purpose of this study was to assess the potential of lipophilic antioxidant coenzyme Q10 (CoQ10) as a scavenger of reactive oxygen species (ROS) to increase sensitivity to temozolomide (TMZ) and suppress glioma cell invasion. To that end, we used a previously established TMZ-resistant RC6 rat glioma cell line, characterized by increased production of ROS, altered antioxidative capacity, and high invasion potential. CoQ10 in combination with TMZ exerted a synergistic antiproliferative effect. These results were confirmed in a 3D model of microfluidic devices showing that the CoQ10 and TMZ combination is more cytotoxic to RC6 cells than TMZ monotherapy. In addition, cotreatment with TMZ increased expression of mitochondrial antioxidant enzymes in RC6 cells. The anti-invasive potential of the combined treatment was shown by gelatin degradation, Matrigel invasion, and 3D spheroid invasion assays as well as in animal models. Inhibition of MMP9 gene expression as well as decreased N-cadherin and vimentin protein expression implied that CoQ10 can suppress invasiveness and the epithelial to mesenchymal transition in RC6 cells. Therefore, our data provide evidences in favor of CoQ10 supplementation to standard GBM treatment due to its potential to inhibit GBM invasion through modulation of the antioxidant capacity.",
journal = "Oxidative Medicine and Cellular Longevity",
title = "Modulation of Antioxidant Potential with Coenzyme Q10 Suppressed Invasion of Temozolomide-Resistant Rat Glioma In Vitro and In Vivo.",
volume = "2019",
doi = "10.1155/2019/3061607",
pages = "3061607"
}

Stojković Burić, S., Podolski-Renić, A., Dinić, J., Stanković, T., Jovanović, M., Hadžić, S., Ayuso, J. M., Virumbrales-Muñoz, M., Fernández, L. J., Ochoa, I., Pérez-García, V. M.,& Pešić, M.. (2019). Modulation of Antioxidant Potential with Coenzyme Q10 Suppressed Invasion of Temozolomide-Resistant Rat Glioma In Vitro and In Vivo.. in Oxidative Medicine and Cellular Longevity, 2019, 3061607.
https://doi.org/10.1155/2019/3061607

Stojković Burić S, Podolski-Renić A, Dinić J, Stanković T, Jovanović M, Hadžić S, Ayuso JM, Virumbrales-Muñoz M, Fernández LJ, Ochoa I, Pérez-García VM, Pešić M. Modulation of Antioxidant Potential with Coenzyme Q10 Suppressed Invasion of Temozolomide-Resistant Rat Glioma In Vitro and In Vivo.. in Oxidative Medicine and Cellular Longevity. 2019;2019:3061607.
doi:10.1155/2019/3061607 .

Stojković Burić, Sonja, Podolski-Renić, Ana, Dinić, Jelena, Stanković, Tijana, Jovanović, Mirna, Hadžić, Stefan, Ayuso, Jose M., Virumbrales-Muñoz, María, Fernández, Luis J., Ochoa, Ignacio, Pérez-García, Victor M., Pešić, Milica, "Modulation of Antioxidant Potential with Coenzyme Q10 Suppressed Invasion of Temozolomide-Resistant Rat Glioma In Vitro and In Vivo." in Oxidative Medicine and Cellular Longevity, 2019 (2019):3061607,
https://doi.org/10.1155/2019/3061607 . .

TY  - JOUR
AU  - Dragoj, Miodrag
AU  - Banković, Jasna
AU  - Podolski-Renić, Ana
AU  - Stojković Burić, Sonja
AU  - Pešić, Milica
AU  - Tanić, Nikola
AU  - Stanković, Tijana
PY  - 2019
UR  - https://content.sciendo.com/view/journals/jomb/ahead-of-print/article-10.2478-jomb-2018-0022.xml
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3099
AB  - Background: C-Myc is one of the major cellular oncogenes overexpressed in non-small cell lung carcinoma (NSCLC). Its deregulated expression is necessary but not sufficient for malignant transformation. We evaluated expression of MYC gene in NSCLC patients and its association with alterations in the genes previously identified to be related to NSCLC pathogenesis, PHACTR3 and E2F4. Methods: We analyzed MYC gene expression by qRT-PCR in 30 NSCLC patients' samples and paired normal lung tissue. MYC expression was further statistically evaluated in relation to histopathological parameters, PHACTR3 and E2F4 gene alterations and survival. Alterations in aforementioned genes were previously detected and identified based on AP-PCR profiles of paired normal and tumor DNA samples, selection of DNA bands with altered mobility in tumor samples and their characterization by the reamplification, cloning and sequencing. Results: MYC expression was significantly increased in NSCLC samples and its overexpression significantly associated with squamous cell carcinoma subtype. Most importantly, MYC overexpression significantly coincided with mutations in PHACTR3 and E2F4 genes, in group of all patients and in squamous cell carcinoma subtype. Moreover, patients with jointly overexpressed MYC and altered PHACTR3 or E2F4 showed trend of shorter survival. Conclusions: Overall, MYC is frequently overexpressed in NSCLC and it is associated with mutated PHACTR3 gene, as well as mutated E2F4 gene. These joint gene alterations could be considered as potential molecular markers of NSCLC and its specific subtypes.
T2  - Journal of Medical Biochemistry
T1  - Association of Overexpressed MYC Gene with Altered PHACTR3 and E2F4 Genes Contributes to Non-Small Cell Lung Carcinoma Pathogenesis
VL  - 37
DO  - 10.2478/jomb-2018-0022
SP  - 188
EP  - 195
ER  - 

@article{
author = "Dragoj, Miodrag and Banković, Jasna and Podolski-Renić, Ana and Stojković Burić, Sonja and Pešić, Milica and Tanić, Nikola and Stanković, Tijana",
year = "2019",
abstract = "Background: C-Myc is one of the major cellular oncogenes overexpressed in non-small cell lung carcinoma (NSCLC). Its deregulated expression is necessary but not sufficient for malignant transformation. We evaluated expression of MYC gene in NSCLC patients and its association with alterations in the genes previously identified to be related to NSCLC pathogenesis, PHACTR3 and E2F4. Methods: We analyzed MYC gene expression by qRT-PCR in 30 NSCLC patients' samples and paired normal lung tissue. MYC expression was further statistically evaluated in relation to histopathological parameters, PHACTR3 and E2F4 gene alterations and survival. Alterations in aforementioned genes were previously detected and identified based on AP-PCR profiles of paired normal and tumor DNA samples, selection of DNA bands with altered mobility in tumor samples and their characterization by the reamplification, cloning and sequencing. Results: MYC expression was significantly increased in NSCLC samples and its overexpression significantly associated with squamous cell carcinoma subtype. Most importantly, MYC overexpression significantly coincided with mutations in PHACTR3 and E2F4 genes, in group of all patients and in squamous cell carcinoma subtype. Moreover, patients with jointly overexpressed MYC and altered PHACTR3 or E2F4 showed trend of shorter survival. Conclusions: Overall, MYC is frequently overexpressed in NSCLC and it is associated with mutated PHACTR3 gene, as well as mutated E2F4 gene. These joint gene alterations could be considered as potential molecular markers of NSCLC and its specific subtypes.",
journal = "Journal of Medical Biochemistry",
title = "Association of Overexpressed MYC Gene with Altered PHACTR3 and E2F4 Genes Contributes to Non-Small Cell Lung Carcinoma Pathogenesis",
volume = "37",
doi = "10.2478/jomb-2018-0022",
pages = "188-195"
}

Dragoj, M., Banković, J., Podolski-Renić, A., Stojković Burić, S., Pešić, M., Tanić, N.,& Stanković, T.. (2019). Association of Overexpressed MYC Gene with Altered PHACTR3 and E2F4 Genes Contributes to Non-Small Cell Lung Carcinoma Pathogenesis. in Journal of Medical Biochemistry, 37, 188-195.
https://doi.org/10.2478/jomb-2018-0022

Dragoj M, Banković J, Podolski-Renić A, Stojković Burić S, Pešić M, Tanić N, Stanković T. Association of Overexpressed MYC Gene with Altered PHACTR3 and E2F4 Genes Contributes to Non-Small Cell Lung Carcinoma Pathogenesis. in Journal of Medical Biochemistry. 2019;37:188-195.
doi:10.2478/jomb-2018-0022 .

Dragoj, Miodrag, Banković, Jasna, Podolski-Renić, Ana, Stojković Burić, Sonja, Pešić, Milica, Tanić, Nikola, Stanković, Tijana, "Association of Overexpressed MYC Gene with Altered PHACTR3 and E2F4 Genes Contributes to Non-Small Cell Lung Carcinoma Pathogenesis" in Journal of Medical Biochemistry, 37 (2019):188-195,
https://doi.org/10.2478/jomb-2018-0022 . .

TY  - JOUR
AU  - Stanković, Tijana
AU  - Dinić, Jelena
AU  - Podolski-Renić, Ana
AU  - Musso, Loana
AU  - Stojković Burić, Sonja
AU  - Dallavalle, Sabrina
AU  - Pešić, Milica
PY  - 2019
UR  - http://www.eurekaselect.com/162878/article
UR  - https://radar.ibiss.bg.ac.rs/123456789/3875
AB  - Background: Dual-targeting in cancer treatment by a single drug is an unconventional approach in relation to drug combinations. The rationale for the development of dualtargeting agents is to overcome incomplete efficacy and drug resistance frequently present when applying individual targeting agents. Consequently, -a more favorable outcome of cancer treatment is expected with dual-targeting strategies. Methods: We reviewed the literature, concentrating on the association between clinically relevant and/or novel dual inhibitors with the potential to modulate multidrug resistant phenotype of cancer cells, particularly the activity of P-glycoprotein. A balanced analysis of content was performed to emphasize the most important findings and optimize the structure of this review. Results: Two-hundred and forty-five papers were included in the review. The introductory part was interpreted by 9 papers. Tyrosine kinase inhibitors’ role in the inhibition of Pglycoprotein and chemosensitization was illustrated by 87 papers. The contribution of naturalbased compounds in overcoming multidrug resistance was reviewed using 92 papers, while specific dual inhibitors acting against microtubule assembling and/or topoisomerases were described with 55 papers. Eleven papers gave an insight into a novel and less explored approach with hybrid drugs. Their influence on P-glycoprotein and multidrug resistance was also evaluated. Conclusion: These findings bring into focus rational anticancer strategies with dual-targeting agents. Most evaluated synthetic and natural drugs showed a great potential in chemosensitization. Further steps in this direction are needed for the optimization of anticancer treatment.
PB  - Sharjah: Bentham Science Publishers
T2  - Current Medicinal Chemistry
T1  - Dual Inhibitors as a New Challenge for Cancer Multidrug Resistance Treatment
IS  - 33
VL  - 26
DO  - 10.2174/0929867325666180607094856
SP  - 6074
EP  - 6106
ER  - 

@article{
author = "Stanković, Tijana and Dinić, Jelena and Podolski-Renić, Ana and Musso, Loana and Stojković Burić, Sonja and Dallavalle, Sabrina and Pešić, Milica",
year = "2019",
abstract = "Background: Dual-targeting in cancer treatment by a single drug is an unconventional approach in relation to drug combinations. The rationale for the development of dualtargeting agents is to overcome incomplete efficacy and drug resistance frequently present when applying individual targeting agents. Consequently, -a more favorable outcome of cancer treatment is expected with dual-targeting strategies. Methods: We reviewed the literature, concentrating on the association between clinically relevant and/or novel dual inhibitors with the potential to modulate multidrug resistant phenotype of cancer cells, particularly the activity of P-glycoprotein. A balanced analysis of content was performed to emphasize the most important findings and optimize the structure of this review. Results: Two-hundred and forty-five papers were included in the review. The introductory part was interpreted by 9 papers. Tyrosine kinase inhibitors’ role in the inhibition of Pglycoprotein and chemosensitization was illustrated by 87 papers. The contribution of naturalbased compounds in overcoming multidrug resistance was reviewed using 92 papers, while specific dual inhibitors acting against microtubule assembling and/or topoisomerases were described with 55 papers. Eleven papers gave an insight into a novel and less explored approach with hybrid drugs. Their influence on P-glycoprotein and multidrug resistance was also evaluated. Conclusion: These findings bring into focus rational anticancer strategies with dual-targeting agents. Most evaluated synthetic and natural drugs showed a great potential in chemosensitization. Further steps in this direction are needed for the optimization of anticancer treatment.",
publisher = "Sharjah: Bentham Science Publishers",
journal = "Current Medicinal Chemistry",
title = "Dual Inhibitors as a New Challenge for Cancer Multidrug Resistance Treatment",
number = "33",
volume = "26",
doi = "10.2174/0929867325666180607094856",
pages = "6074-6106"
}

Stanković, T., Dinić, J., Podolski-Renić, A., Musso, L., Stojković Burić, S., Dallavalle, S.,& Pešić, M.. (2019). Dual Inhibitors as a New Challenge for Cancer Multidrug Resistance Treatment. in Current Medicinal Chemistry
Sharjah: Bentham Science Publishers., 26(33), 6074-6106.
https://doi.org/10.2174/0929867325666180607094856

Stanković T, Dinić J, Podolski-Renić A, Musso L, Stojković Burić S, Dallavalle S, Pešić M. Dual Inhibitors as a New Challenge for Cancer Multidrug Resistance Treatment. in Current Medicinal Chemistry. 2019;26(33):6074-6106.
doi:10.2174/0929867325666180607094856 .

Stanković, Tijana, Dinić, Jelena, Podolski-Renić, Ana, Musso, Loana, Stojković Burić, Sonja, Dallavalle, Sabrina, Pešić, Milica, "Dual Inhibitors as a New Challenge for Cancer Multidrug Resistance Treatment" in Current Medicinal Chemistry, 26, no. 33 (2019):6074-6106,
https://doi.org/10.2174/0929867325666180607094856 . .

TY  - JOUR
AU  - Stanković, Tijana
AU  - Dinić, Jelena
AU  - Podolski-Renić, Ana
AU  - Musso, Loana
AU  - Stojković Burić, Sonja
AU  - Dallavalle, Sabrina
AU  - Pešić, Milica
PY  - 2019
UR  - http://www.eurekaselect.com/162878/article
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3567
AB  - BACKGROUND Dual-targeting in cancer treatment by a single drug is an unconventional approach in relation to drug combinations. The rationale for the development of dualtargeting agents is to overcome incomplete efficacy and drug resistance frequently present when applying individual targeting agents. Consequently, -a more favorable outcome of cancer treatment is expected with dual-targeting strategies. METHODS We reviewed the literature, concentrating on the association between clinically relevant and/or novel dual inhibitors with the potential to modulate multidrug resistant phenotype of cancer cells, particularly the activity of P-glycoprotein. A balanced analysis of content was performed to emphasize the most important findings and optimize the structure of this review. RESULTS Two-hundred and forty-five papers were included in the review. The introductory part was interpreted by 9 papers. Tyrosine kinase inhibitors' role in the inhibition of Pglycoprotein and chemosensitization was illustrated by 87 papers. The contribution of naturalbased compounds in overcoming multidrug resistance was reviewed using 92 papers, while specific dual inhibitors acting against microtubule assembling and/or topoisomerases were described with 55 papers. Eleven papers gave an insight into a novel and less explored approach with hybrid drugs. Their influence on P-glycoprotein and multidrug resistance was also evaluated. CONCLUSION These findings bring into focus rational anticancer strategies with dual-targeting agents. Most evaluated synthetic and natural drugs showed a great potential in chemosensitization. Further steps in this direction are needed for the optimization of anticancer treatment.
T2  - Current Medicinal Chemistry
T1  - Dual Inhibitors as a New Challenge for Cancer Multidrug Resistance Treatment.
IS  - 33
VL  - 26
DO  - 10.2174/0929867325666180607094856
SP  - 6074
EP  - 6106
ER  - 

@article{
author = "Stanković, Tijana and Dinić, Jelena and Podolski-Renić, Ana and Musso, Loana and Stojković Burić, Sonja and Dallavalle, Sabrina and Pešić, Milica",
year = "2019",
abstract = "BACKGROUND Dual-targeting in cancer treatment by a single drug is an unconventional approach in relation to drug combinations. The rationale for the development of dualtargeting agents is to overcome incomplete efficacy and drug resistance frequently present when applying individual targeting agents. Consequently, -a more favorable outcome of cancer treatment is expected with dual-targeting strategies. METHODS We reviewed the literature, concentrating on the association between clinically relevant and/or novel dual inhibitors with the potential to modulate multidrug resistant phenotype of cancer cells, particularly the activity of P-glycoprotein. A balanced analysis of content was performed to emphasize the most important findings and optimize the structure of this review. RESULTS Two-hundred and forty-five papers were included in the review. The introductory part was interpreted by 9 papers. Tyrosine kinase inhibitors' role in the inhibition of Pglycoprotein and chemosensitization was illustrated by 87 papers. The contribution of naturalbased compounds in overcoming multidrug resistance was reviewed using 92 papers, while specific dual inhibitors acting against microtubule assembling and/or topoisomerases were described with 55 papers. Eleven papers gave an insight into a novel and less explored approach with hybrid drugs. Their influence on P-glycoprotein and multidrug resistance was also evaluated. CONCLUSION These findings bring into focus rational anticancer strategies with dual-targeting agents. Most evaluated synthetic and natural drugs showed a great potential in chemosensitization. Further steps in this direction are needed for the optimization of anticancer treatment.",
journal = "Current Medicinal Chemistry",
title = "Dual Inhibitors as a New Challenge for Cancer Multidrug Resistance Treatment.",
number = "33",
volume = "26",
doi = "10.2174/0929867325666180607094856",
pages = "6074-6106"
}

Stanković, T., Dinić, J., Podolski-Renić, A., Musso, L., Stojković Burić, S., Dallavalle, S.,& Pešić, M.. (2019). Dual Inhibitors as a New Challenge for Cancer Multidrug Resistance Treatment.. in Current Medicinal Chemistry, 26(33), 6074-6106.
https://doi.org/10.2174/0929867325666180607094856

Stanković T, Dinić J, Podolski-Renić A, Musso L, Stojković Burić S, Dallavalle S, Pešić M. Dual Inhibitors as a New Challenge for Cancer Multidrug Resistance Treatment.. in Current Medicinal Chemistry. 2019;26(33):6074-6106.
doi:10.2174/0929867325666180607094856 .

Stanković, Tijana, Dinić, Jelena, Podolski-Renić, Ana, Musso, Loana, Stojković Burić, Sonja, Dallavalle, Sabrina, Pešić, Milica, "Dual Inhibitors as a New Challenge for Cancer Multidrug Resistance Treatment." in Current Medicinal Chemistry, 26, no. 33 (2019):6074-6106,
https://doi.org/10.2174/0929867325666180607094856 . .

TY  - JOUR
AU  - Podolski-Renić, Ana
AU  - Dinić, Jelena
AU  - Stanković, Tijana
AU  - Jovanović, Mirna
AU  - Ramović, Amra
AU  - Pustenko, Aleksandrs
AU  - Žalubovskis, Raivis
AU  - Pešić, Milica
PY  - 2019
UR  - https://www.sciencedirect.com/science/article/pii/S0928098719302751?dgcid=coauthor
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3441
AB  - New 6-triazolyl-substituted sulfocoumarins were described as potent inhibitors of the transmembrane human carbonic anhydrase isoforms, CAIX and CAXII. These membrane associated enzymes that maintain pH and CO2 homeostasis are involved in cancer progression, invasion, and resistance to therapy. Recently, it was shown that CAXII expression associates with the expression of P-glycoprotein in multidrug resistant cancer cells. CAXII regulates P-glycoprotein activity by maintaining high intracellular pHi. In this study, the activity of three new sulfocoumarins was evaluated in three sensitive and corresponding multidrug resistant cancer cell lines with increased P-glycoprotein expression (non-small cell lung carcinoma, colorectal carcinoma and glioblastoma). Compound 3 showed the highest potential for cancer cell growth inhibition in all tested cell lines. Flow cytometric analyses showed that compound 3 induced intracellular acidification, cell cycle arrest in G2/M phase and necrosis in non-small cell lung carcinoma cells. Compound 3 demonstrated irreversible, concentration- and time-dependent inhibition of P-glycoprotein activity in multidrug resistant non-small cell lung carcinoma cells. The suppression of P-glycoprotein activity was accompanied with increased P-glycoprotein expression suggesting a compensatory mechanism of multidrug resistant cancer cells. In addition, compound 3 was able to sensitize multidrug resistant non-small cell lung carcinoma cells to doxorubicin. Overall, results imply that compound 3 has multidrug resistance modulating effect through intracellular acidification and subsequent inhibition of P-glycoprotein activity.
T2  - European Journal of Pharmaceutical Sciences
T1  - Sulfocoumarins, specific carbonic anhydrase IX and XII inhibitors, interact with cancer multidrug resistant phenotype through pH regulation and reverse P-glycoprotein mediated resistance.
VL  - 138
DO  - 10.1016/j.ejps.2019.105012
SP  - 105012
ER  - 

@article{
author = "Podolski-Renić, Ana and Dinić, Jelena and Stanković, Tijana and Jovanović, Mirna and Ramović, Amra and Pustenko, Aleksandrs and Žalubovskis, Raivis and Pešić, Milica",
year = "2019",
abstract = "New 6-triazolyl-substituted sulfocoumarins were described as potent inhibitors of the transmembrane human carbonic anhydrase isoforms, CAIX and CAXII. These membrane associated enzymes that maintain pH and CO2 homeostasis are involved in cancer progression, invasion, and resistance to therapy. Recently, it was shown that CAXII expression associates with the expression of P-glycoprotein in multidrug resistant cancer cells. CAXII regulates P-glycoprotein activity by maintaining high intracellular pHi. In this study, the activity of three new sulfocoumarins was evaluated in three sensitive and corresponding multidrug resistant cancer cell lines with increased P-glycoprotein expression (non-small cell lung carcinoma, colorectal carcinoma and glioblastoma). Compound 3 showed the highest potential for cancer cell growth inhibition in all tested cell lines. Flow cytometric analyses showed that compound 3 induced intracellular acidification, cell cycle arrest in G2/M phase and necrosis in non-small cell lung carcinoma cells. Compound 3 demonstrated irreversible, concentration- and time-dependent inhibition of P-glycoprotein activity in multidrug resistant non-small cell lung carcinoma cells. The suppression of P-glycoprotein activity was accompanied with increased P-glycoprotein expression suggesting a compensatory mechanism of multidrug resistant cancer cells. In addition, compound 3 was able to sensitize multidrug resistant non-small cell lung carcinoma cells to doxorubicin. Overall, results imply that compound 3 has multidrug resistance modulating effect through intracellular acidification and subsequent inhibition of P-glycoprotein activity.",
journal = "European Journal of Pharmaceutical Sciences",
title = "Sulfocoumarins, specific carbonic anhydrase IX and XII inhibitors, interact with cancer multidrug resistant phenotype through pH regulation and reverse P-glycoprotein mediated resistance.",
volume = "138",
doi = "10.1016/j.ejps.2019.105012",
pages = "105012"
}

Podolski-Renić, A., Dinić, J., Stanković, T., Jovanović, M., Ramović, A., Pustenko, A., Žalubovskis, R.,& Pešić, M.. (2019). Sulfocoumarins, specific carbonic anhydrase IX and XII inhibitors, interact with cancer multidrug resistant phenotype through pH regulation and reverse P-glycoprotein mediated resistance.. in European Journal of Pharmaceutical Sciences, 138, 105012.
https://doi.org/10.1016/j.ejps.2019.105012

Podolski-Renić A, Dinić J, Stanković T, Jovanović M, Ramović A, Pustenko A, Žalubovskis R, Pešić M. Sulfocoumarins, specific carbonic anhydrase IX and XII inhibitors, interact with cancer multidrug resistant phenotype through pH regulation and reverse P-glycoprotein mediated resistance.. in European Journal of Pharmaceutical Sciences. 2019;138:105012.
doi:10.1016/j.ejps.2019.105012 .

Podolski-Renić, Ana, Dinić, Jelena, Stanković, Tijana, Jovanović, Mirna, Ramović, Amra, Pustenko, Aleksandrs, Žalubovskis, Raivis, Pešić, Milica, "Sulfocoumarins, specific carbonic anhydrase IX and XII inhibitors, interact with cancer multidrug resistant phenotype through pH regulation and reverse P-glycoprotein mediated resistance." in European Journal of Pharmaceutical Sciences, 138 (2019):105012,
https://doi.org/10.1016/j.ejps.2019.105012 . .

TY  - JOUR
AU  - Fallacara, Ana Lucia
AU  - Zamperini, Claudio
AU  - Podolski-Renić, Ana
AU  - Dinić, Jelena
AU  - Stanković, Tijana
AU  - Nešović, Marija
AU  - Mancini, Arianna
AU  - Rango, Enrico
AU  - Iovenitti, Giulia
AU  - Molinari, Alessio
AU  - Bugli, Francesca
AU  - Sanguinetti, Maurizio
AU  - Torelli, Riccardo
AU  - Martini, Maurizio
AU  - Maccari, Laura
AU  - Valoti, Massimo
AU  - Dreassi, Elena
AU  - Botta, Maurizio
AU  - Pešić, Milica
AU  - Schenone, Silvia
PY  - 2019
UR  - https://www.mdpi.com/2072-6694/11/6/848
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3379
AB  - Overexpression of P-glycoprotein (P-gp) and other ATP-binding cassette (ABC) transporters
in multidrug resistant (MDR) cancer cells is responsible for the reduction of intracellular drug
accumulation, thus decreasing the efficacy of chemotherapeutics. P-gp is also found at endothelial
cells’ membrane of the blood-brain barrier, where it limits drug delivery to central nervous system
(CNS) tumors. We have previously developed a set of pyrazolo[3,4-d]pyrimidines and their prodrugs
as novel Src tyrosine kinase inhibitors (TKIs), showing a significant activity against CNS tumors in
in vivo. Here we investigated the interaction of the most promising pair of drug/prodrug with P-gp
at the cellular level. The tested compounds were found to increase the intracellular accumulation
of Rho 123, and to enhance the efficacy of paclitaxel in P-gp overexpressing cells. Encouraging
pharmacokinetics properties and tolerability in vivo were also observed. Our findings revealed a
novel role of pyrazolo[3,4-d]pyrimidines which may be useful for developing a new effective therapy
in MDR cancer treatment, particularly against glioblastoma.
T2  - Cancers
T1  - A New Strategy for Glioblastoma Treatment: In Vitro and In Vivo Preclinical Characterization of Si306, a Pyrazolo[3,4-d]Pyrimidine Dual Src/P-Glycoprotein Inhibitor
IS  - 6
VL  - 11
DO  - 10.3390/cancers11060848
SP  - 848
ER  - 

@article{
author = "Fallacara, Ana Lucia and Zamperini, Claudio and Podolski-Renić, Ana and Dinić, Jelena and Stanković, Tijana and Nešović, Marija and Mancini, Arianna and Rango, Enrico and Iovenitti, Giulia and Molinari, Alessio and Bugli, Francesca and Sanguinetti, Maurizio and Torelli, Riccardo and Martini, Maurizio and Maccari, Laura and Valoti, Massimo and Dreassi, Elena and Botta, Maurizio and Pešić, Milica and Schenone, Silvia",
year = "2019",
abstract = "Overexpression of P-glycoprotein (P-gp) and other ATP-binding cassette (ABC) transporters
in multidrug resistant (MDR) cancer cells is responsible for the reduction of intracellular drug
accumulation, thus decreasing the efficacy of chemotherapeutics. P-gp is also found at endothelial
cells’ membrane of the blood-brain barrier, where it limits drug delivery to central nervous system
(CNS) tumors. We have previously developed a set of pyrazolo[3,4-d]pyrimidines and their prodrugs
as novel Src tyrosine kinase inhibitors (TKIs), showing a significant activity against CNS tumors in
in vivo. Here we investigated the interaction of the most promising pair of drug/prodrug with P-gp
at the cellular level. The tested compounds were found to increase the intracellular accumulation
of Rho 123, and to enhance the efficacy of paclitaxel in P-gp overexpressing cells. Encouraging
pharmacokinetics properties and tolerability in vivo were also observed. Our findings revealed a
novel role of pyrazolo[3,4-d]pyrimidines which may be useful for developing a new effective therapy
in MDR cancer treatment, particularly against glioblastoma.",
journal = "Cancers",
title = "A New Strategy for Glioblastoma Treatment: In Vitro and In Vivo Preclinical Characterization of Si306, a Pyrazolo[3,4-d]Pyrimidine Dual Src/P-Glycoprotein Inhibitor",
number = "6",
volume = "11",
doi = "10.3390/cancers11060848",
pages = "848"
}

Fallacara, A. L., Zamperini, C., Podolski-Renić, A., Dinić, J., Stanković, T., Nešović, M., Mancini, A., Rango, E., Iovenitti, G., Molinari, A., Bugli, F., Sanguinetti, M., Torelli, R., Martini, M., Maccari, L., Valoti, M., Dreassi, E., Botta, M., Pešić, M.,& Schenone, S.. (2019). A New Strategy for Glioblastoma Treatment: In Vitro and In Vivo Preclinical Characterization of Si306, a Pyrazolo[3,4-d]Pyrimidine Dual Src/P-Glycoprotein Inhibitor. in Cancers, 11(6), 848.
https://doi.org/10.3390/cancers11060848

Fallacara AL, Zamperini C, Podolski-Renić A, Dinić J, Stanković T, Nešović M, Mancini A, Rango E, Iovenitti G, Molinari A, Bugli F, Sanguinetti M, Torelli R, Martini M, Maccari L, Valoti M, Dreassi E, Botta M, Pešić M, Schenone S. A New Strategy for Glioblastoma Treatment: In Vitro and In Vivo Preclinical Characterization of Si306, a Pyrazolo[3,4-d]Pyrimidine Dual Src/P-Glycoprotein Inhibitor. in Cancers. 2019;11(6):848.
doi:10.3390/cancers11060848 .

Fallacara, Ana Lucia, Zamperini, Claudio, Podolski-Renić, Ana, Dinić, Jelena, Stanković, Tijana, Nešović, Marija, Mancini, Arianna, Rango, Enrico, Iovenitti, Giulia, Molinari, Alessio, Bugli, Francesca, Sanguinetti, Maurizio, Torelli, Riccardo, Martini, Maurizio, Maccari, Laura, Valoti, Massimo, Dreassi, Elena, Botta, Maurizio, Pešić, Milica, Schenone, Silvia, "A New Strategy for Glioblastoma Treatment: In Vitro and In Vivo Preclinical Characterization of Si306, a Pyrazolo[3,4-d]Pyrimidine Dual Src/P-Glycoprotein Inhibitor" in Cancers, 11, no. 6 (2019):848,
https://doi.org/10.3390/cancers11060848 . .

TY  - JOUR
AU  - Garcia, Catarina
AU  - Ntungwe, Epole
AU  - Rebelo, Ana
AU  - Bessa, Cláudia
AU  - Stanković, Tijana
AU  - Dinić, Jelena
AU  - Díaz-Lanza, Ana
AU  - P Reis, Catarina
AU  - Roberto, Amílcar
AU  - Pereira, Paula
AU  - Cebola, Maria-João
AU  - Saraiva, Lucília
AU  - Pešić, Milica
AU  - Duarte, Noélia
AU  - Rijo, Patrícia
PY  - 2019
UR  - https://www.mdpi.com/2218-273X/9/10/616
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3492
AB  - The Plectranthus genus is commonly used in traditional medicine due to its potential to treat several illnesses, including bacterial infections and cancer. As such, aiming to screen the antibacterial and cytotoxic activities of extracts, sixteen selected Plectranthus species with medicinal potential were studied. In total, 31 extracts obtained from 16 Plectranthus spp. were tested for their antibacterial and anticancer properties. Well diffusion method was used for preliminary antibacterial screening. The minimum inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) values of the five most active acetonic extracts (P. aliciae, P. japonicus, P. madagascariensis var. "Lynne", P. stylesii, and P. strigosus) were determined. After preliminary toxicity evaluation on Artemia salina L., their cytotoxic properties were assessed on three human cancer cell lines (HCT116, MCF-7, and H460). These were also selected for mechanism of resistance studies (on NCI-H460/R and DLD1-TxR cells). An identified compound-parvifloron D-was tested in a pair of sensitive and MDR-Multidrug resistance cancer cells (NCI-H460 and NCI-H460/R) and in normal bronchial fibroblasts MRC-5. The chemical composition of the most active extract was studied through high performance liquid chromatography with a diode array detector (HPLC-DAD/UV) and liquid chromatography-mass spectrometry (LC-MS). Overall, P. strigosus acetonic extract showed the strongest antimicrobial and cytotoxic potential that could be explained by the presence of parvifloron D, a highly cytotoxic diterpene. This study provides valuable information on the use of the Plectranthus genus as a source of bioactive compounds, namely P. strigosus with the potential active ingredient the parvifloron D.
T2  - Biomolecules
T1  - Parvifloron D from Plectranthusstrigosus: Cytotoxicity Screening of Plectranthus spp. Extracts.
IS  - 10
VL  - 9
DO  - 10.3390/biom9100616
SP  - 616
ER  - 

@article{
author = "Garcia, Catarina and Ntungwe, Epole and Rebelo, Ana and Bessa, Cláudia and Stanković, Tijana and Dinić, Jelena and Díaz-Lanza, Ana and P Reis, Catarina and Roberto, Amílcar and Pereira, Paula and Cebola, Maria-João and Saraiva, Lucília and Pešić, Milica and Duarte, Noélia and Rijo, Patrícia",
year = "2019",
abstract = "The Plectranthus genus is commonly used in traditional medicine due to its potential to treat several illnesses, including bacterial infections and cancer. As such, aiming to screen the antibacterial and cytotoxic activities of extracts, sixteen selected Plectranthus species with medicinal potential were studied. In total, 31 extracts obtained from 16 Plectranthus spp. were tested for their antibacterial and anticancer properties. Well diffusion method was used for preliminary antibacterial screening. The minimum inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) values of the five most active acetonic extracts (P. aliciae, P. japonicus, P. madagascariensis var. "Lynne", P. stylesii, and P. strigosus) were determined. After preliminary toxicity evaluation on Artemia salina L., their cytotoxic properties were assessed on three human cancer cell lines (HCT116, MCF-7, and H460). These were also selected for mechanism of resistance studies (on NCI-H460/R and DLD1-TxR cells). An identified compound-parvifloron D-was tested in a pair of sensitive and MDR-Multidrug resistance cancer cells (NCI-H460 and NCI-H460/R) and in normal bronchial fibroblasts MRC-5. The chemical composition of the most active extract was studied through high performance liquid chromatography with a diode array detector (HPLC-DAD/UV) and liquid chromatography-mass spectrometry (LC-MS). Overall, P. strigosus acetonic extract showed the strongest antimicrobial and cytotoxic potential that could be explained by the presence of parvifloron D, a highly cytotoxic diterpene. This study provides valuable information on the use of the Plectranthus genus as a source of bioactive compounds, namely P. strigosus with the potential active ingredient the parvifloron D.",
journal = "Biomolecules",
title = "Parvifloron D from Plectranthusstrigosus: Cytotoxicity Screening of Plectranthus spp. Extracts.",
number = "10",
volume = "9",
doi = "10.3390/biom9100616",
pages = "616"
}

Garcia, C., Ntungwe, E., Rebelo, A., Bessa, C., Stanković, T., Dinić, J., Díaz-Lanza, A., P Reis, C., Roberto, A., Pereira, P., Cebola, M., Saraiva, L., Pešić, M., Duarte, N.,& Rijo, P.. (2019). Parvifloron D from Plectranthusstrigosus: Cytotoxicity Screening of Plectranthus spp. Extracts.. in Biomolecules, 9(10), 616.
https://doi.org/10.3390/biom9100616

Garcia C, Ntungwe E, Rebelo A, Bessa C, Stanković T, Dinić J, Díaz-Lanza A, P Reis C, Roberto A, Pereira P, Cebola M, Saraiva L, Pešić M, Duarte N, Rijo P. Parvifloron D from Plectranthusstrigosus: Cytotoxicity Screening of Plectranthus spp. Extracts.. in Biomolecules. 2019;9(10):616.
doi:10.3390/biom9100616 .

Garcia, Catarina, Ntungwe, Epole, Rebelo, Ana, Bessa, Cláudia, Stanković, Tijana, Dinić, Jelena, Díaz-Lanza, Ana, P Reis, Catarina, Roberto, Amílcar, Pereira, Paula, Cebola, Maria-João, Saraiva, Lucília, Pešić, Milica, Duarte, Noélia, Rijo, Patrícia, "Parvifloron D from Plectranthusstrigosus: Cytotoxicity Screening of Plectranthus spp. Extracts." in Biomolecules, 9, no. 10 (2019):616,
https://doi.org/10.3390/biom9100616 . .

TY  - JOUR
AU  - Matias, Diogo
AU  - Nicolai, Marisa
AU  - Saraiva, Lucília
AU  - Pinheiro, Rute
AU  - Faustino, Célia
AU  - Diaz Lanza, Ana
AU  - Pinto Reis, Catarina
AU  - Stanković, Tijana
AU  - Dinić, Jelena
AU  - Pešić, Milica
AU  - Rijo, Patrícia
PY  - 2019
UR  - http://pubs.acs.org/doi/10.1021/acsomega.9b00512
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3349
AB  - Cytotoxicity screenings have identified Plectranthus plants as potential sources of antitumor lead compounds. In this work, several extracts from Plectranthus madagascariensis were prepared using different solvents (acetone, methanol, and supercritical CO2) and extraction techniques (maceration, ultrasound-assisted, and supercritical fluid extraction), and their chemical composition was detailed using high-performance liquid chromatography with a diode array detector. The cytotoxic activity of the major compounds identified, namely, rosmarinic acid (1) and abietane diterpenes 7α,6β-dihydroxyroyleanone (2), 7α-formyloxy-6β-hydroxyroyleanone (3), 7α-acetoxy-6β-hydroxyroyleanone (4), and coleon U (5), was evaluated in a battery of human cancer cell lines, including breast (MDA-MB-231, MCF-7), colon (HCT116), and lung (NCI-H460, NCI-H460/R) cancer, and also in healthy lung (MCR-5) cells. Royleanone (3) was isolated for the first time from P. madagascariensis, and its full spectroscopic characterization (proto...
T2  - ACS Omega
T1  - Cytotoxic Activity of Royleanone Diterpenes from <i>Plectranthus madagascariensis</i> Benth
IS  - 5
VL  - 4
DO  - 10.1021/acsomega.9b00512
SP  - 8094
EP  - 8103
ER  - 

@article{
author = "Matias, Diogo and Nicolai, Marisa and Saraiva, Lucília and Pinheiro, Rute and Faustino, Célia and Diaz Lanza, Ana and Pinto Reis, Catarina and Stanković, Tijana and Dinić, Jelena and Pešić, Milica and Rijo, Patrícia",
year = "2019",
abstract = "Cytotoxicity screenings have identified Plectranthus plants as potential sources of antitumor lead compounds. In this work, several extracts from Plectranthus madagascariensis were prepared using different solvents (acetone, methanol, and supercritical CO2) and extraction techniques (maceration, ultrasound-assisted, and supercritical fluid extraction), and their chemical composition was detailed using high-performance liquid chromatography with a diode array detector. The cytotoxic activity of the major compounds identified, namely, rosmarinic acid (1) and abietane diterpenes 7α,6β-dihydroxyroyleanone (2), 7α-formyloxy-6β-hydroxyroyleanone (3), 7α-acetoxy-6β-hydroxyroyleanone (4), and coleon U (5), was evaluated in a battery of human cancer cell lines, including breast (MDA-MB-231, MCF-7), colon (HCT116), and lung (NCI-H460, NCI-H460/R) cancer, and also in healthy lung (MCR-5) cells. Royleanone (3) was isolated for the first time from P. madagascariensis, and its full spectroscopic characterization (proto...",
journal = "ACS Omega",
title = "Cytotoxic Activity of Royleanone Diterpenes from <i>Plectranthus madagascariensis</i> Benth",
number = "5",
volume = "4",
doi = "10.1021/acsomega.9b00512",
pages = "8094-8103"
}

Matias, D., Nicolai, M., Saraiva, L., Pinheiro, R., Faustino, C., Diaz Lanza, A., Pinto Reis, C., Stanković, T., Dinić, J., Pešić, M.,& Rijo, P.. (2019). Cytotoxic Activity of Royleanone Diterpenes from <i>Plectranthus madagascariensis</i> Benth. in ACS Omega, 4(5), 8094-8103.
https://doi.org/10.1021/acsomega.9b00512

Matias D, Nicolai M, Saraiva L, Pinheiro R, Faustino C, Diaz Lanza A, Pinto Reis C, Stanković T, Dinić J, Pešić M, Rijo P. Cytotoxic Activity of Royleanone Diterpenes from <i>Plectranthus madagascariensis</i> Benth. in ACS Omega. 2019;4(5):8094-8103.
doi:10.1021/acsomega.9b00512 .

Matias, Diogo, Nicolai, Marisa, Saraiva, Lucília, Pinheiro, Rute, Faustino, Célia, Diaz Lanza, Ana, Pinto Reis, Catarina, Stanković, Tijana, Dinić, Jelena, Pešić, Milica, Rijo, Patrícia, "Cytotoxic Activity of Royleanone Diterpenes from <i>Plectranthus madagascariensis</i> Benth" in ACS Omega, 4, no. 5 (2019):8094-8103,
https://doi.org/10.1021/acsomega.9b00512 . .

TY  - CONF
AU  - Nešović, Marija
AU  - Garcia, Catarina
AU  - Stanković, Tijana
AU  - Dinić, Jelena
AU  - Podolski-Renić, Ana
AU  - Stojkovic Burić, Sonja
AU  - Dragoj, Miodrag
AU  - Jovanović, Mirna
AU  - Rijo, Patricia
AU  - Pešić, Milica
PY  - 2018
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6434
AB  - The genus Plectranthus has been widely used in traditional medicine to treat numerous diseases, including cancer. In this study, 31 extracts obtained from 16 Plectranthus spp. with medicinal potential were evaluated for their anticancer properties. The cytotoxic effects of all extracts were assessed in non-small cell lung carcinoma cell line NCI-H460. Five most promising Plectranthus spp. extracts (P. aliciae, P. japonicus, P. malvinus, P. stylesii and P. strigosus) were additionally tested for growth inhibition activity in multidrug resistant (MDR) cell lines with P-glycoprotein overexpression: NCI-H460/R (non-small cell lung carcinoma) and DLD1-TxR (colorectal adenocarcinoma), and compared to their sensitive counterparts, NCI-H460 and DLD1. P. strigosus acetonic extract was shown to be the most active. Parvifloron D, a diterpene identified in this extract, was tested in NCI-H460 and NCI-H460/R cells, as well as normal human embryonic bronchial fibroblasts (MRC-5) to evaluate its selectivity against cancer cells. It displayed the same efficacy in sensitive and MDR cancer cells, implying that parvifloron D is not a substrate for P-glycoprotein. Flow-cytometric analysis revealed that while parvifloron D is not exported via the P glycoprotein, it does not possess the potential to inhibit this transporter’s activity in NCI-H460/R cells. This study provides valuable information on the use of the Plectranthus genus as a source of therapeutically useful compounds against cancer cells including those with MDR phenotype, as well as compounds potentially responsible for their activity such as abietane diterpene parvifloron D. Additionally, the bioactivities of several Plectranthus spp. not previously described are reported.
PB  - Belgrade: Serbian Plant Physiology Society
C3  - Book of abstracts. 3rd International Conference on Plant Biology (22nd SPPS Meeting); 2018 Jun 9-12; Belgrade, Serbia
T1  - Evaluation of anticancer activity of Plectranthus spp. extracts
SP  - 149
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6434
ER  - 

@conference{
author = "Nešović, Marija and Garcia, Catarina and Stanković, Tijana and Dinić, Jelena and Podolski-Renić, Ana and Stojkovic Burić, Sonja and Dragoj, Miodrag and Jovanović, Mirna and Rijo, Patricia and Pešić, Milica",
year = "2018",
abstract = "The genus Plectranthus has been widely used in traditional medicine to treat numerous diseases, including cancer. In this study, 31 extracts obtained from 16 Plectranthus spp. with medicinal potential were evaluated for their anticancer properties. The cytotoxic effects of all extracts were assessed in non-small cell lung carcinoma cell line NCI-H460. Five most promising Plectranthus spp. extracts (P. aliciae, P. japonicus, P. malvinus, P. stylesii and P. strigosus) were additionally tested for growth inhibition activity in multidrug resistant (MDR) cell lines with P-glycoprotein overexpression: NCI-H460/R (non-small cell lung carcinoma) and DLD1-TxR (colorectal adenocarcinoma), and compared to their sensitive counterparts, NCI-H460 and DLD1. P. strigosus acetonic extract was shown to be the most active. Parvifloron D, a diterpene identified in this extract, was tested in NCI-H460 and NCI-H460/R cells, as well as normal human embryonic bronchial fibroblasts (MRC-5) to evaluate its selectivity against cancer cells. It displayed the same efficacy in sensitive and MDR cancer cells, implying that parvifloron D is not a substrate for P-glycoprotein. Flow-cytometric analysis revealed that while parvifloron D is not exported via the P glycoprotein, it does not possess the potential to inhibit this transporter’s activity in NCI-H460/R cells. This study provides valuable information on the use of the Plectranthus genus as a source of therapeutically useful compounds against cancer cells including those with MDR phenotype, as well as compounds potentially responsible for their activity such as abietane diterpene parvifloron D. Additionally, the bioactivities of several Plectranthus spp. not previously described are reported.",
publisher = "Belgrade: Serbian Plant Physiology Society",
journal = "Book of abstracts. 3rd International Conference on Plant Biology (22nd SPPS Meeting); 2018 Jun 9-12; Belgrade, Serbia",
title = "Evaluation of anticancer activity of Plectranthus spp. extracts",
pages = "149",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6434"
}

Nešović, M., Garcia, C., Stanković, T., Dinić, J., Podolski-Renić, A., Stojkovic Burić, S., Dragoj, M., Jovanović, M., Rijo, P.,& Pešić, M.. (2018). Evaluation of anticancer activity of Plectranthus spp. extracts. in Book of abstracts. 3rd International Conference on Plant Biology (22nd SPPS Meeting); 2018 Jun 9-12; Belgrade, Serbia
Belgrade: Serbian Plant Physiology Society., 149.
https://hdl.handle.net/21.15107/rcub_ibiss_6434

Nešović M, Garcia C, Stanković T, Dinić J, Podolski-Renić A, Stojkovic Burić S, Dragoj M, Jovanović M, Rijo P, Pešić M. Evaluation of anticancer activity of Plectranthus spp. extracts. in Book of abstracts. 3rd International Conference on Plant Biology (22nd SPPS Meeting); 2018 Jun 9-12; Belgrade, Serbia. 2018;:149.
https://hdl.handle.net/21.15107/rcub_ibiss_6434 .

Nešović, Marija, Garcia, Catarina, Stanković, Tijana, Dinić, Jelena, Podolski-Renić, Ana, Stojkovic Burić, Sonja, Dragoj, Miodrag, Jovanović, Mirna, Rijo, Patricia, Pešić, Milica, "Evaluation of anticancer activity of Plectranthus spp. extracts" in Book of abstracts. 3rd International Conference on Plant Biology (22nd SPPS Meeting); 2018 Jun 9-12; Belgrade, Serbia (2018):149,
https://hdl.handle.net/21.15107/rcub_ibiss_6434 .

TY  - CONF
AU  - Nešović, Marija
AU  - Garcia, Catarina
AU  - Stanković, Tijana
AU  - Dinić, Jelena
AU  - Podolski-Renić, Ana
AU  - Stojković Burić, Sonja
AU  - Dragoj, Miodrag
AU  - Jovanović, Mirna
AU  - Rijo, Patricia
AU  - Pešić, Milica
PY  - 2018
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6433
AB  - Natural compound-based green chemistry has been the focus of current nanobiotechnology
research to improve efficacy and safety of medicines through targeted drug delivery. The Lamiaceae family, widely used in traditional medicine, is a well-known source of natural compounds with
anticancer properties. A wide spectrum of bioactive diterpenes have been isolated from the genus Plectranthus, including 6,7-dehydroroyleanone (DHR), a abietane found in the essential oil of P.
madagascariensis. The biological activity of DHR was investigated in P-glycoprotein-overexpressing multidrug resistant (MDR) non-small cell lung cancer cell line (NCI-H460/R), its sensitive counterpart (NCI-H460) and normal human embryonic bronchial epithelial cells (MRC-5). DHR showed
significant growth inhibition and slight selectivity against cancer cell lines when compared to
normal cells. The results also confirmed that DHR is not a substrate for P-glycoprotein as it does
not interfere with its activity. This diterpene was incorporated into Hybrid nanoparticles in order
to increase treatment efficacy and delivery selectivity. Anticancer properties of this nanosystem
were compared to the activity of DHR alone. Additionally, to address the problem of multidrug
resistance, this nanosystem was tested against cancer cells with MDR phenotype. Coupling of
DHR with Hybrid nanoparticles additionally improved the cytotoxicity of DHR, decreasing the IC50
value 8-fold in NCI-H460 cells and 5-fold in NCI-H460/R cells. These findings imply that combining
natural products, such as DHR, with nanoparticles could be considered as a promising anticancer
strategy with potential to overcome drug resistance.
PB  - Belgrade: Serbian Plant Physiology Society; Institute for Biological Research "Siniša Stanković"; Faculty of Biology
C3  - Book of abstracts. 3rd International Conference on Plant Biology (22nd SPPS Meeting); 2018 Jun 9-12; Belgrade, Serbia
T1  - Anticancer properties of the abietane diterpene 6,7-dehydroroyleanone from Plectranthus madagascariensis
SP  - 150
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6433
ER  - 

@conference{
author = "Nešović, Marija and Garcia, Catarina and Stanković, Tijana and Dinić, Jelena and Podolski-Renić, Ana and Stojković Burić, Sonja and Dragoj, Miodrag and Jovanović, Mirna and Rijo, Patricia and Pešić, Milica",
year = "2018",
abstract = "Natural compound-based green chemistry has been the focus of current nanobiotechnology
research to improve efficacy and safety of medicines through targeted drug delivery. The Lamiaceae family, widely used in traditional medicine, is a well-known source of natural compounds with
anticancer properties. A wide spectrum of bioactive diterpenes have been isolated from the genus Plectranthus, including 6,7-dehydroroyleanone (DHR), a abietane found in the essential oil of P.
madagascariensis. The biological activity of DHR was investigated in P-glycoprotein-overexpressing multidrug resistant (MDR) non-small cell lung cancer cell line (NCI-H460/R), its sensitive counterpart (NCI-H460) and normal human embryonic bronchial epithelial cells (MRC-5). DHR showed
significant growth inhibition and slight selectivity against cancer cell lines when compared to
normal cells. The results also confirmed that DHR is not a substrate for P-glycoprotein as it does
not interfere with its activity. This diterpene was incorporated into Hybrid nanoparticles in order
to increase treatment efficacy and delivery selectivity. Anticancer properties of this nanosystem
were compared to the activity of DHR alone. Additionally, to address the problem of multidrug
resistance, this nanosystem was tested against cancer cells with MDR phenotype. Coupling of
DHR with Hybrid nanoparticles additionally improved the cytotoxicity of DHR, decreasing the IC50
value 8-fold in NCI-H460 cells and 5-fold in NCI-H460/R cells. These findings imply that combining
natural products, such as DHR, with nanoparticles could be considered as a promising anticancer
strategy with potential to overcome drug resistance.",
publisher = "Belgrade: Serbian Plant Physiology Society; Institute for Biological Research "Siniša Stanković"; Faculty of Biology",
journal = "Book of abstracts. 3rd International Conference on Plant Biology (22nd SPPS Meeting); 2018 Jun 9-12; Belgrade, Serbia",
title = "Anticancer properties of the abietane diterpene 6,7-dehydroroyleanone from Plectranthus madagascariensis",
pages = "150",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6433"
}

Nešović, M., Garcia, C., Stanković, T., Dinić, J., Podolski-Renić, A., Stojković Burić, S., Dragoj, M., Jovanović, M., Rijo, P.,& Pešić, M.. (2018). Anticancer properties of the abietane diterpene 6,7-dehydroroyleanone from Plectranthus madagascariensis. in Book of abstracts. 3rd International Conference on Plant Biology (22nd SPPS Meeting); 2018 Jun 9-12; Belgrade, Serbia
Belgrade: Serbian Plant Physiology Society; Institute for Biological Research "Siniša Stanković"; Faculty of Biology., 150.
https://hdl.handle.net/21.15107/rcub_ibiss_6433

Nešović M, Garcia C, Stanković T, Dinić J, Podolski-Renić A, Stojković Burić S, Dragoj M, Jovanović M, Rijo P, Pešić M. Anticancer properties of the abietane diterpene 6,7-dehydroroyleanone from Plectranthus madagascariensis. in Book of abstracts. 3rd International Conference on Plant Biology (22nd SPPS Meeting); 2018 Jun 9-12; Belgrade, Serbia. 2018;:150.
https://hdl.handle.net/21.15107/rcub_ibiss_6433 .

Nešović, Marija, Garcia, Catarina, Stanković, Tijana, Dinić, Jelena, Podolski-Renić, Ana, Stojković Burić, Sonja, Dragoj, Miodrag, Jovanović, Mirna, Rijo, Patricia, Pešić, Milica, "Anticancer properties of the abietane diterpene 6,7-dehydroroyleanone from Plectranthus madagascariensis" in Book of abstracts. 3rd International Conference on Plant Biology (22nd SPPS Meeting); 2018 Jun 9-12; Belgrade, Serbia (2018):150,
https://hdl.handle.net/21.15107/rcub_ibiss_6433 .