TY  - JOUR
AU  - Prvanović, Mirjana
AU  - Nedeljković, Milica
AU  - Tanić, Nasta
AU  - Tomić, Tijana
AU  - Terzić, Tanja
AU  - Milovanović, Zorka
AU  - Maksimović, Zlatko
AU  - Tanić, Nikola
PY  - 2021
UR  - https://www.mdpi.com/2075-1729/11/11/1247
UR  - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC8621563
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/4698
AB  - Breast cancer is the most commonly occurring malignancy and the leading cause of cancer-related death in women. Triple-negative breast cancer (TNBC) is the most aggressive subtype and is associated with high recurrence rates, high incidence of distant metastases, and poor overall survival. The aim of this study was to investigate the PI3K/PTEN/Akt/mTOR pathway as one of the most frequently deregulated pathways in cancer. We aimed to explore the impact of PI3K and mTOR oncogenes as well as the PTEN tumor suppressor on TNBC clinical behavior, prognosis, and multidrug resistance (MDR), using immunohistochemistry and copy number analysis by quantitative real-time PCR. Our results revealed that loss of PTEN and high expression of PI3K and mTOR proteins are associated with poor outcome of TNBC patients. PTEN deletions appeared as a major cause of reduced or absent PTEN expression in TNBC. Importantly, homozygous deletions of PTEN (and not hemizygous deletions) are a potential molecular marker of metastasis formation and good predictors of TNBC outcome. In conclusion, we believe that concurrent examination of PTEN/PI3K/mTOR protein expression may be more useful in predicting TNBC clinical course than the analysis of single protein expression. Specifically, our results showed that PTEN-reduced/PI3K-high/mTOR-high expression constitutes a 'high risk' profile of TNBC.
PB  - Basel: MDPI
T2  - Life (Basel, Switzerland)
T1  - Role of PTEN, PI3K, and mTOR in Triple-Negative Breast Cancer.
IS  - 11
VL  - 11
DO  - 10.3390/life11111247
SP  - 1247
ER  - 

@article{
author = "Prvanović, Mirjana and Nedeljković, Milica and Tanić, Nasta and Tomić, Tijana and Terzić, Tanja and Milovanović, Zorka and Maksimović, Zlatko and Tanić, Nikola",
year = "2021",
abstract = "Breast cancer is the most commonly occurring malignancy and the leading cause of cancer-related death in women. Triple-negative breast cancer (TNBC) is the most aggressive subtype and is associated with high recurrence rates, high incidence of distant metastases, and poor overall survival. The aim of this study was to investigate the PI3K/PTEN/Akt/mTOR pathway as one of the most frequently deregulated pathways in cancer. We aimed to explore the impact of PI3K and mTOR oncogenes as well as the PTEN tumor suppressor on TNBC clinical behavior, prognosis, and multidrug resistance (MDR), using immunohistochemistry and copy number analysis by quantitative real-time PCR. Our results revealed that loss of PTEN and high expression of PI3K and mTOR proteins are associated with poor outcome of TNBC patients. PTEN deletions appeared as a major cause of reduced or absent PTEN expression in TNBC. Importantly, homozygous deletions of PTEN (and not hemizygous deletions) are a potential molecular marker of metastasis formation and good predictors of TNBC outcome. In conclusion, we believe that concurrent examination of PTEN/PI3K/mTOR protein expression may be more useful in predicting TNBC clinical course than the analysis of single protein expression. Specifically, our results showed that PTEN-reduced/PI3K-high/mTOR-high expression constitutes a 'high risk' profile of TNBC.",
publisher = "Basel: MDPI",
journal = "Life (Basel, Switzerland)",
title = "Role of PTEN, PI3K, and mTOR in Triple-Negative Breast Cancer.",
number = "11",
volume = "11",
doi = "10.3390/life11111247",
pages = "1247"
}

Prvanović, M., Nedeljković, M., Tanić, N., Tomić, T., Terzić, T., Milovanović, Z., Maksimović, Z.,& Tanić, N.. (2021). Role of PTEN, PI3K, and mTOR in Triple-Negative Breast Cancer.. in Life (Basel, Switzerland)
Basel: MDPI., 11(11), 1247.
https://doi.org/10.3390/life11111247

Prvanović M, Nedeljković M, Tanić N, Tomić T, Terzić T, Milovanović Z, Maksimović Z, Tanić N. Role of PTEN, PI3K, and mTOR in Triple-Negative Breast Cancer.. in Life (Basel, Switzerland). 2021;11(11):1247.
doi:10.3390/life11111247 .

Prvanović, Mirjana, Nedeljković, Milica, Tanić, Nasta, Tomić, Tijana, Terzić, Tanja, Milovanović, Zorka, Maksimović, Zlatko, Tanić, Nikola, "Role of PTEN, PI3K, and mTOR in Triple-Negative Breast Cancer." in Life (Basel, Switzerland), 11, no. 11 (2021):1247,
https://doi.org/10.3390/life11111247 . .

TY  - JOUR
AU  - Nedeljković, Milica
AU  - Tanić, Nasta
AU  - Prvanović, Mirjana
AU  - Milovanović, Zorka
AU  - Tanić, Nikola
PY  - 2021
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4233
AB  - Background: ATP-binding cassette (ABC) transporters are responsible for the efflux of a wide variety of anti-cancer agents and have been implicated in the chemoresistance of various solid tumors. Chemoresistance is a major cause of therapeutic failure, especially in the highly aggressive triple-negative breast cancer (TNBC) in which, unlike estrogen receptor-expressing (ER+) BC, both endocrine and targeted treatments are ineffectual. We aimed to investigate the level and frequency of expression of the three most important ABC transporter, ABCG2, ABCC1, and ABCB1, according to breast cancer subtype. Methods: We evaluated ABCG2, ABCC1, and ABCB1 protein expressions in 124 primary breast tumors (78 samples were classified as TNBC, while 46 were classified as ER+) by immunohistochemistry and correlated it to clinicopathological characteristics and outcome. Results: All three transporters had significantly higher expression and were more frequently expressed in TNBC compared to ER+ tumors (p < 0.0001). ABCG2 and ABCC1 had a very high level of expression in TNBC that was significantly greater compared to ABCB1 (p < 0.0001). ABCB1 expression was associated with TNBC metastatic spread (p = 0.03). In contrast, TNBC patients with high ABCG2 expression level had significantly longer disease-free interval (p = 0.03) and overall survival (p = 0.007). Conclusion: ABCG2, ABCC1, and ABCB1 expression in breast cancer is subtype-specific and associated with triple-negative tumors. The expression of ABCB1 may be useful as a marker of metastatic spread. Moreover, unexpectedly, our results showed a beneficial effect of ABCG2 expression on TNBC clinical behavior. These findings could have implications for the implementation of future TNBC treatment strategies.
PB  - Springer Japan
T2  - Breast Cancer
T1  - Friend or foe: ABCG2, ABCC1 and ABCB1 expression in triple-negative breast cancer
IS  - 3
VL  - 28
DO  - 10.1007/s12282-020-01210-z
SP  - 727
EP  - 736
ER  - 

@article{
author = "Nedeljković, Milica and Tanić, Nasta and Prvanović, Mirjana and Milovanović, Zorka and Tanić, Nikola",
year = "2021",
abstract = "Background: ATP-binding cassette (ABC) transporters are responsible for the efflux of a wide variety of anti-cancer agents and have been implicated in the chemoresistance of various solid tumors. Chemoresistance is a major cause of therapeutic failure, especially in the highly aggressive triple-negative breast cancer (TNBC) in which, unlike estrogen receptor-expressing (ER+) BC, both endocrine and targeted treatments are ineffectual. We aimed to investigate the level and frequency of expression of the three most important ABC transporter, ABCG2, ABCC1, and ABCB1, according to breast cancer subtype. Methods: We evaluated ABCG2, ABCC1, and ABCB1 protein expressions in 124 primary breast tumors (78 samples were classified as TNBC, while 46 were classified as ER+) by immunohistochemistry and correlated it to clinicopathological characteristics and outcome. Results: All three transporters had significantly higher expression and were more frequently expressed in TNBC compared to ER+ tumors (p < 0.0001). ABCG2 and ABCC1 had a very high level of expression in TNBC that was significantly greater compared to ABCB1 (p < 0.0001). ABCB1 expression was associated with TNBC metastatic spread (p = 0.03). In contrast, TNBC patients with high ABCG2 expression level had significantly longer disease-free interval (p = 0.03) and overall survival (p = 0.007). Conclusion: ABCG2, ABCC1, and ABCB1 expression in breast cancer is subtype-specific and associated with triple-negative tumors. The expression of ABCB1 may be useful as a marker of metastatic spread. Moreover, unexpectedly, our results showed a beneficial effect of ABCG2 expression on TNBC clinical behavior. These findings could have implications for the implementation of future TNBC treatment strategies.",
publisher = "Springer Japan",
journal = "Breast Cancer",
title = "Friend or foe: ABCG2, ABCC1 and ABCB1 expression in triple-negative breast cancer",
number = "3",
volume = "28",
doi = "10.1007/s12282-020-01210-z",
pages = "727-736"
}

Nedeljković, M., Tanić, N., Prvanović, M., Milovanović, Z.,& Tanić, N.. (2021). Friend or foe: ABCG2, ABCC1 and ABCB1 expression in triple-negative breast cancer. in Breast Cancer
Springer Japan., 28(3), 727-736.
https://doi.org/10.1007/s12282-020-01210-z

Nedeljković M, Tanić N, Prvanović M, Milovanović Z, Tanić N. Friend or foe: ABCG2, ABCC1 and ABCB1 expression in triple-negative breast cancer. in Breast Cancer. 2021;28(3):727-736.
doi:10.1007/s12282-020-01210-z .

Nedeljković, Milica, Tanić, Nasta, Prvanović, Mirjana, Milovanović, Zorka, Tanić, Nikola, "Friend or foe: ABCG2, ABCC1 and ABCB1 expression in triple-negative breast cancer" in Breast Cancer, 28, no. 3 (2021):727-736,
https://doi.org/10.1007/s12282-020-01210-z . .

TY  - THES
AU  - Jovanović, Mirna
PY  - 2021
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4422
AB  - Tioredoksinski sistem, ćelijski redoks regulator, ima važnu ulogu u nastanku tumora, progresiji, metastazi i sticanju rezistencije na lekove. Povišena ekspresija tioredoksin-reduktaze 1 (TrxR1) je u korelaciji sa stepenom maligniteta glioblastoma i neuroblastoma. Cilj ove disertacije bio je ispitivanje potencijala Ugi-tipa Majklovih akceptora (UMA) – inhibitora TrxR1 za lečenje glioblastoma i neuroblastoma, kao i u prevazilaženju višestruke rezistencije na hemioterapeutike. Shodno tome, ispitana je efikasnost UMA u inhibiciji TrxR1; zatim, dejstvo UMA inhibitora na rast ćelija neuroblastoma, glioblastoma i normalnih ćelija. Pokazano je da UMA inhibitori snažnije inhibiraju rast proliferišućih ćelija (neuroblastoma, glioblastoma i keratinocita) u odnosu na neproliferišuće mononuklearne ćelije krvi. Mehanizam antitumorskog dejstva dva najpotentnija inhibitora, DVD-444 i DVD-445, je ispitan na senzitivnim i rezistentnim ćelijama glioma. UMA inhibitori su prouzrokovali oksidativni stres, depolarizaciju mitohondrija i povišenu ekspresiju antioksidativnih enzima u ćelijama glioma. Utvrđeno je da imaju citotoksično, antiproliferativno i antiinvazivno dejstvo na ćelije glioma, kao i da povećavaju njihovu osetljivost na temozolomid. UMA inhibitori su suprimirali aktivnost P-glikoproteina (P-gp) i povećali osetljivost rezistentnih ćelija glioma na paklitaksel. Okarakterisani su antitumorski efekti serije inhibitora TrxR1 analognih DVD-445. Analozi DVD-445, su indukovali oksidativni stres, ćelijsku smrt i inhibirali aktivnost P-gp u ćelijama glioma u većoj meri od DVD-445. Rezultati ove disertacije ukazuju da je inhibicija TrxR1 perpsektivna strategija za lečenje glioblastoma i neuroblastoma, i da su UMA inhibitori TrxR1 dobri kandidati za razvoj novih hemioterapeutika.
AB  - Thioredoxin system, cell redox regulator, has important role in tumor development, progression, metastasis and chemoresistance. Thioredoxin reductase 1 (TrxR1) high expression is in correlation with glioblastoma and neuroblastoma malignancy. Goal of this dissertation was investigating potential of Ugy-type Michael acceptors (UMAs) – TrxR1 inhibitors, for glioblastoma and neuroblastoma treatment, as well as in overcoming multidrug resistance. Accordingly, potential of TrxR1 inhibition by UMA was tested in vitro, followed by testing of UMA inhibitors on cell growth of neuroblastoma, glioblastoma and normal cells. UMA inhibitors demonstrated a stronger inhibitory effect on proliferating cells (neuroblastoma, glioblastoma, keratinocytes) in comparison to non-proliferating blood mononuclear cells. Antitumor effect mechanism of two most potent compounds, DVD-444 and DVD-445, was tested in sensitive and resistant glioma cells. UMA inhibitors caused oxidative stress, mitochondrial depolarisation and elevated expression of antioxidant enzymes in glioma cells, showed cytotoxic, antiproliferative and anti-invasive effect, and sensitized glioma cells to temozolomide. UMA inhibitors suppressed P-glycoprotein (P-gp) activity and sensitized resistant glioma cells to paclitaxel. Antitumor effects of DVD-445 analogue compounds were investigated. DVD-445 analogues induced oxidative stress, cell death and inhibited P-gp activity in glioma cells, at greater extent than DVD-445. Results presented here suggest that TrxR1 inhibition is a promising strategy in treating glioblastoma and neuroblastoma and that UMA inhibitors are aspiring candidates for novel chemotherapy development.
PB  - Belgrade: Faculty of Biology, University of Belgrade
T2  - Faculty of Biology, University of Belgrade
T1  - Razvoj antitumorske strategije primenom inhibicije tioredoksin-reduktaze 1 u ćelijskim modelima glioblastoma i neuroblastoma
T1  - Development of antitumor strategy by inhibition of thioredoxin reductase 1 in cell models of glioblastoma and neuroblastoma
SP  - 1
EP  - 105
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_4422
ER  - 

@phdthesis{
author = "Jovanović, Mirna",
year = "2021",
abstract = "Tioredoksinski sistem, ćelijski redoks regulator, ima važnu ulogu u nastanku tumora, progresiji, metastazi i sticanju rezistencije na lekove. Povišena ekspresija tioredoksin-reduktaze 1 (TrxR1) je u korelaciji sa stepenom maligniteta glioblastoma i neuroblastoma. Cilj ove disertacije bio je ispitivanje potencijala Ugi-tipa Majklovih akceptora (UMA) – inhibitora TrxR1 za lečenje glioblastoma i neuroblastoma, kao i u prevazilaženju višestruke rezistencije na hemioterapeutike. Shodno tome, ispitana je efikasnost UMA u inhibiciji TrxR1; zatim, dejstvo UMA inhibitora na rast ćelija neuroblastoma, glioblastoma i normalnih ćelija. Pokazano je da UMA inhibitori snažnije inhibiraju rast proliferišućih ćelija (neuroblastoma, glioblastoma i keratinocita) u odnosu na neproliferišuće mononuklearne ćelije krvi. Mehanizam antitumorskog dejstva dva najpotentnija inhibitora, DVD-444 i DVD-445, je ispitan na senzitivnim i rezistentnim ćelijama glioma. UMA inhibitori su prouzrokovali oksidativni stres, depolarizaciju mitohondrija i povišenu ekspresiju antioksidativnih enzima u ćelijama glioma. Utvrđeno je da imaju citotoksično, antiproliferativno i antiinvazivno dejstvo na ćelije glioma, kao i da povećavaju njihovu osetljivost na temozolomid. UMA inhibitori su suprimirali aktivnost P-glikoproteina (P-gp) i povećali osetljivost rezistentnih ćelija glioma na paklitaksel. Okarakterisani su antitumorski efekti serije inhibitora TrxR1 analognih DVD-445. Analozi DVD-445, su indukovali oksidativni stres, ćelijsku smrt i inhibirali aktivnost P-gp u ćelijama glioma u većoj meri od DVD-445. Rezultati ove disertacije ukazuju da je inhibicija TrxR1 perpsektivna strategija za lečenje glioblastoma i neuroblastoma, i da su UMA inhibitori TrxR1 dobri kandidati za razvoj novih hemioterapeutika., Thioredoxin system, cell redox regulator, has important role in tumor development, progression, metastasis and chemoresistance. Thioredoxin reductase 1 (TrxR1) high expression is in correlation with glioblastoma and neuroblastoma malignancy. Goal of this dissertation was investigating potential of Ugy-type Michael acceptors (UMAs) – TrxR1 inhibitors, for glioblastoma and neuroblastoma treatment, as well as in overcoming multidrug resistance. Accordingly, potential of TrxR1 inhibition by UMA was tested in vitro, followed by testing of UMA inhibitors on cell growth of neuroblastoma, glioblastoma and normal cells. UMA inhibitors demonstrated a stronger inhibitory effect on proliferating cells (neuroblastoma, glioblastoma, keratinocytes) in comparison to non-proliferating blood mononuclear cells. Antitumor effect mechanism of two most potent compounds, DVD-444 and DVD-445, was tested in sensitive and resistant glioma cells. UMA inhibitors caused oxidative stress, mitochondrial depolarisation and elevated expression of antioxidant enzymes in glioma cells, showed cytotoxic, antiproliferative and anti-invasive effect, and sensitized glioma cells to temozolomide. UMA inhibitors suppressed P-glycoprotein (P-gp) activity and sensitized resistant glioma cells to paclitaxel. Antitumor effects of DVD-445 analogue compounds were investigated. DVD-445 analogues induced oxidative stress, cell death and inhibited P-gp activity in glioma cells, at greater extent than DVD-445. Results presented here suggest that TrxR1 inhibition is a promising strategy in treating glioblastoma and neuroblastoma and that UMA inhibitors are aspiring candidates for novel chemotherapy development.",
publisher = "Belgrade: Faculty of Biology, University of Belgrade",
journal = "Faculty of Biology, University of Belgrade",
title = "Razvoj antitumorske strategije primenom inhibicije tioredoksin-reduktaze 1 u ćelijskim modelima glioblastoma i neuroblastoma, Development of antitumor strategy by inhibition of thioredoxin reductase 1 in cell models of glioblastoma and neuroblastoma",
pages = "1-105",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_4422"
}

Jovanović, M.. (2021). Razvoj antitumorske strategije primenom inhibicije tioredoksin-reduktaze 1 u ćelijskim modelima glioblastoma i neuroblastoma. in Faculty of Biology, University of Belgrade
Belgrade: Faculty of Biology, University of Belgrade., 1-105.
https://hdl.handle.net/21.15107/rcub_ibiss_4422

Jovanović M. Razvoj antitumorske strategije primenom inhibicije tioredoksin-reduktaze 1 u ćelijskim modelima glioblastoma i neuroblastoma. in Faculty of Biology, University of Belgrade. 2021;:1-105.
https://hdl.handle.net/21.15107/rcub_ibiss_4422 .

Jovanović, Mirna, "Razvoj antitumorske strategije primenom inhibicije tioredoksin-reduktaze 1 u ćelijskim modelima glioblastoma i neuroblastoma" in Faculty of Biology, University of Belgrade (2021):1-105,
https://hdl.handle.net/21.15107/rcub_ibiss_4422 .

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  - JOUR
AU  - Dinić, Jelena
AU  - Ríos-Luci, Carla
AU  - Karpaviciene, Ieva
AU  - Cikotiene, Inga
AU  - Fernandes, Miguel X.
AU  - Pešić, Milica
AU  - Padrón, José M.
PY  - 2020
UR  - http://link.springer.com/10.1007/s10637-019-00803-6
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3393
AB  - Microtubule targeting agents (MTAs) are extensively used in cancer treatment and many have achieved substantial clinical success. In recent years, targeting microtubules to inhibit cell division has become a widespread pharmaceutical approach for treatment of various cancer types. Nevertheless, the development of multidrug resistance (MDR) in cancer remains a major obstacle for successful application of these agents. Herein, we provided the evidence that CKT0353, α-branched α,β-unsaturated ketone, possesses the capacity to successfully evade the MDR phenotype as an MTA. CKT0353 induced G2/M phase arrest, delayed cell division via spindle assembly checkpoint activation, disrupted the mitotic spindle formation and depolymerized microtubules in human breast, cervix, and colorectal carcinoma cells. Molecular docking analysis revealed that CKT0353 binds at the nocodazole binding domain of β-tubulin. Furthermore, CKT0353 triggered apoptosis via caspase-dependent mechanism. In addition, P-glycoprotein overexpressing colorectal carcinoma cells showed higher sensitivity to this agent when compared to their sensitive counterpart, demonstrating the ability of CKT0353 to overcome this classic MDR mechanism involved in resistance to various MTAs. Taken together, these findings suggest that CKT0353 is an excellent candidate for further optimization as a therapeutic agent against tumors with MDR phenotype.
T2  - Investigational New Drugs
T2  - Investigational New Drugs
T1  - CKT0353, a novel microtubule targeting agent, overcomes paclitaxel induced resistance in cancer cells.
VL  - 38
DO  - 10.1007/s10637-019-00803-6
SP  - 584
EP  - 598
ER  - 

@article{
author = "Dinić, Jelena and Ríos-Luci, Carla and Karpaviciene, Ieva and Cikotiene, Inga and Fernandes, Miguel X. and Pešić, Milica and Padrón, José M.",
year = "2020",
abstract = "Microtubule targeting agents (MTAs) are extensively used in cancer treatment and many have achieved substantial clinical success. In recent years, targeting microtubules to inhibit cell division has become a widespread pharmaceutical approach for treatment of various cancer types. Nevertheless, the development of multidrug resistance (MDR) in cancer remains a major obstacle for successful application of these agents. Herein, we provided the evidence that CKT0353, α-branched α,β-unsaturated ketone, possesses the capacity to successfully evade the MDR phenotype as an MTA. CKT0353 induced G2/M phase arrest, delayed cell division via spindle assembly checkpoint activation, disrupted the mitotic spindle formation and depolymerized microtubules in human breast, cervix, and colorectal carcinoma cells. Molecular docking analysis revealed that CKT0353 binds at the nocodazole binding domain of β-tubulin. Furthermore, CKT0353 triggered apoptosis via caspase-dependent mechanism. In addition, P-glycoprotein overexpressing colorectal carcinoma cells showed higher sensitivity to this agent when compared to their sensitive counterpart, demonstrating the ability of CKT0353 to overcome this classic MDR mechanism involved in resistance to various MTAs. Taken together, these findings suggest that CKT0353 is an excellent candidate for further optimization as a therapeutic agent against tumors with MDR phenotype.",
journal = "Investigational New Drugs, Investigational New Drugs",
title = "CKT0353, a novel microtubule targeting agent, overcomes paclitaxel induced resistance in cancer cells.",
volume = "38",
doi = "10.1007/s10637-019-00803-6",
pages = "584-598"
}

Dinić, J., Ríos-Luci, C., Karpaviciene, I., Cikotiene, I., Fernandes, M. X., Pešić, M.,& Padrón, J. M.. (2020). CKT0353, a novel microtubule targeting agent, overcomes paclitaxel induced resistance in cancer cells.. in Investigational New Drugs, 38, 584-598.
https://doi.org/10.1007/s10637-019-00803-6

Dinić J, Ríos-Luci C, Karpaviciene I, Cikotiene I, Fernandes MX, Pešić M, Padrón JM. CKT0353, a novel microtubule targeting agent, overcomes paclitaxel induced resistance in cancer cells.. in Investigational New Drugs. 2020;38:584-598.
doi:10.1007/s10637-019-00803-6 .

Dinić, Jelena, Ríos-Luci, Carla, Karpaviciene, Ieva, Cikotiene, Inga, Fernandes, Miguel X., Pešić, Milica, Padrón, José M., "CKT0353, a novel microtubule targeting agent, overcomes paclitaxel induced resistance in cancer cells." in Investigational New Drugs, 38 (2020):584-598,
https://doi.org/10.1007/s10637-019-00803-6 . .

TY  - JOUR
AU  - Venturelli, Leonardo
AU  - Kohler, Anne-Céline
AU  - Stupar, Petar
AU  - Villalba, Maria I.
AU  - Kalauzi, Aleksandar
AU  - Radotić, Ksenija
AU  - Bertacchi, Massimiliano
AU  - Dinarelli, Simone
AU  - Girasole, Marco
AU  - Pešić, Milica
AU  - Banković, Jasna
AU  - Vela, Maria E.
AU  - Yantorno, Osvaldo
AU  - Willaert, Ronnie
AU  - Dietler, Giovanni
AU  - Longo, Giovanni
AU  - Kasas, Sandor
PY  - 2020
UR  - http://doi.wiley.com/10.1002/jmr.2849
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3641
AB  - The insurgence of newly arising, rapidly developing health threats, such as drug-resistant bacteria and cancers, is one of the most urgent public-health issues of modern times. This menace calls for the development of sensitive and reliable diagnostic tools to monitor the response of single cells to chemical or pharmaceutical stimuli. Recently, it has been demonstrated that all living organisms oscillate at a nanometric scale and that these oscillations stop as soon as the organisms die. These nanometric scale oscillations can be detected by depositing living cells onto a micro-fabricated cantilever and by monitoring its displacements with an atomic force microscope-based electronics. Such devices, named nanomotion sensors, have been employed to determine the resistance profiles of life-threatening bacteria within minutes, to evaluate, among others, the effect of chemicals on yeast, neurons, and cancer cells. The data obtained so far demonstrate the advantages of nanomotion sensing devices in rapidly characterizing microorganism susceptibility to pharmaceutical agents. Here, we review the key aspects of this technique, presenting its major applications. and detailing its working protocols.
T2  - Journal of Molecular Recognition
T1  - A perspective view on the nanomotion detection of living organisms and its features
DO  - 10.1002/jmr.2849
SP  - e2849
ER  - 

@article{
author = "Venturelli, Leonardo and Kohler, Anne-Céline and Stupar, Petar and Villalba, Maria I. and Kalauzi, Aleksandar and Radotić, Ksenija and Bertacchi, Massimiliano and Dinarelli, Simone and Girasole, Marco and Pešić, Milica and Banković, Jasna and Vela, Maria E. and Yantorno, Osvaldo and Willaert, Ronnie and Dietler, Giovanni and Longo, Giovanni and Kasas, Sandor",
year = "2020",
abstract = "The insurgence of newly arising, rapidly developing health threats, such as drug-resistant bacteria and cancers, is one of the most urgent public-health issues of modern times. This menace calls for the development of sensitive and reliable diagnostic tools to monitor the response of single cells to chemical or pharmaceutical stimuli. Recently, it has been demonstrated that all living organisms oscillate at a nanometric scale and that these oscillations stop as soon as the organisms die. These nanometric scale oscillations can be detected by depositing living cells onto a micro-fabricated cantilever and by monitoring its displacements with an atomic force microscope-based electronics. Such devices, named nanomotion sensors, have been employed to determine the resistance profiles of life-threatening bacteria within minutes, to evaluate, among others, the effect of chemicals on yeast, neurons, and cancer cells. The data obtained so far demonstrate the advantages of nanomotion sensing devices in rapidly characterizing microorganism susceptibility to pharmaceutical agents. Here, we review the key aspects of this technique, presenting its major applications. and detailing its working protocols.",
journal = "Journal of Molecular Recognition",
title = "A perspective view on the nanomotion detection of living organisms and its features",
doi = "10.1002/jmr.2849",
pages = "e2849"
}

Venturelli, L., Kohler, A., Stupar, P., Villalba, M. I., Kalauzi, A., Radotić, K., Bertacchi, M., Dinarelli, S., Girasole, M., Pešić, M., Banković, J., Vela, M. E., Yantorno, O., Willaert, R., Dietler, G., Longo, G.,& Kasas, S.. (2020). A perspective view on the nanomotion detection of living organisms and its features. in Journal of Molecular Recognition, e2849.
https://doi.org/10.1002/jmr.2849

Venturelli L, Kohler A, Stupar P, Villalba MI, Kalauzi A, Radotić K, Bertacchi M, Dinarelli S, Girasole M, Pešić M, Banković J, Vela ME, Yantorno O, Willaert R, Dietler G, Longo G, Kasas S. A perspective view on the nanomotion detection of living organisms and its features. in Journal of Molecular Recognition. 2020;:e2849.
doi:10.1002/jmr.2849 .

Venturelli, Leonardo, Kohler, Anne-Céline, Stupar, Petar, Villalba, Maria I., Kalauzi, Aleksandar, Radotić, Ksenija, Bertacchi, Massimiliano, Dinarelli, Simone, Girasole, Marco, Pešić, Milica, Banković, Jasna, Vela, Maria E., Yantorno, Osvaldo, Willaert, Ronnie, Dietler, Giovanni, Longo, Giovanni, Kasas, Sandor, "A perspective view on the nanomotion detection of living organisms and its features" in Journal of Molecular Recognition (2020):e2849,
https://doi.org/10.1002/jmr.2849 . .

TY  - JOUR
AU  - Nešović, Marija
AU  - Divac Rankov, Aleksandra
AU  - Podolski-Renić, Ana
AU  - Nikolić, Igor
AU  - Tasić, Goran
AU  - Mancini, Arianna
AU  - Schenone, Silvia
AU  - Pešić, Milica
AU  - Dinić, Jelena
PY  - 2020
UR  - https://www.mdpi.com/2072-6694/12/6/1570
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3818
AB  - Glioblastoma (GBM), as the most aggressive brain tumor, displays a high expression of Src tyrosine kinase, which is involved in the survival, migration, and invasiveness of tumor cells. Thus, Src emerged as a potential target for GBM therapy. The effects of Src inhibitors pyrazolo[3,4-d]pyrimidines, Si306 and its prodrug pro-Si306 were investigated in human GBM cell lines (U87 and U87-TxR) and three primary GBM cell cultures. Primary GBM cells were more resistant to Si306 and pro-Si306 according to the 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. However, the ability of all GBM cells to degrade the extracellular matrix was considerably compromised after Si306 and pro-Si306 applications. Besides reducing the phosphorylation of Src and its downstream signaling pathway components, both compounds decreased the phosphorylated form of focal adhesion kinase (FAK) and epidermal growth factor receptor (EGFR) expression, showing the potential to suppress the aggressiveness of GBM. In vivo, Si306 and pro-Si306 displayed an anti-invasive effect against U87 xenografts in the zebrafish embryo model. Considering that Si306 and pro-Si306 are able to cross the blood-brain barrier and suppress the spread of GBM cells, we anticipate their clinical testing in the near future. Moreover, the prodrug showed similar efficacy to the drug, implying the rationality of its use in clinical settings.
PB  - Basel : MDPI
T2  - Cancers (Basel)
T1  - Src Inhibitors Pyrazolo[3,4-d]pyrimidines, Si306 and Pro-Si306, Inhibit Focal Adhesion Kinase and Suppress Human Glioblastoma Invasion In Vitro and In Vivo
IS  - 6
VL  - 12
DO  - 10.3390/cancers12061570
SP  - 1570
ER  - 

@article{
author = "Nešović, Marija and Divac Rankov, Aleksandra and Podolski-Renić, Ana and Nikolić, Igor and Tasić, Goran and Mancini, Arianna and Schenone, Silvia and Pešić, Milica and Dinić, Jelena",
year = "2020",
abstract = "Glioblastoma (GBM), as the most aggressive brain tumor, displays a high expression of Src tyrosine kinase, which is involved in the survival, migration, and invasiveness of tumor cells. Thus, Src emerged as a potential target for GBM therapy. The effects of Src inhibitors pyrazolo[3,4-d]pyrimidines, Si306 and its prodrug pro-Si306 were investigated in human GBM cell lines (U87 and U87-TxR) and three primary GBM cell cultures. Primary GBM cells were more resistant to Si306 and pro-Si306 according to the 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. However, the ability of all GBM cells to degrade the extracellular matrix was considerably compromised after Si306 and pro-Si306 applications. Besides reducing the phosphorylation of Src and its downstream signaling pathway components, both compounds decreased the phosphorylated form of focal adhesion kinase (FAK) and epidermal growth factor receptor (EGFR) expression, showing the potential to suppress the aggressiveness of GBM. In vivo, Si306 and pro-Si306 displayed an anti-invasive effect against U87 xenografts in the zebrafish embryo model. Considering that Si306 and pro-Si306 are able to cross the blood-brain barrier and suppress the spread of GBM cells, we anticipate their clinical testing in the near future. Moreover, the prodrug showed similar efficacy to the drug, implying the rationality of its use in clinical settings.",
publisher = "Basel : MDPI",
journal = "Cancers (Basel)",
title = "Src Inhibitors Pyrazolo[3,4-d]pyrimidines, Si306 and Pro-Si306, Inhibit Focal Adhesion Kinase and Suppress Human Glioblastoma Invasion In Vitro and In Vivo",
number = "6",
volume = "12",
doi = "10.3390/cancers12061570",
pages = "1570"
}

Nešović, M., Divac Rankov, A., Podolski-Renić, A., Nikolić, I., Tasić, G., Mancini, A., Schenone, S., Pešić, M.,& Dinić, J.. (2020). Src Inhibitors Pyrazolo[3,4-d]pyrimidines, Si306 and Pro-Si306, Inhibit Focal Adhesion Kinase and Suppress Human Glioblastoma Invasion In Vitro and In Vivo. in Cancers (Basel)
Basel : MDPI., 12(6), 1570.
https://doi.org/10.3390/cancers12061570

Nešović M, Divac Rankov A, Podolski-Renić A, Nikolić I, Tasić G, Mancini A, Schenone S, Pešić M, Dinić J. Src Inhibitors Pyrazolo[3,4-d]pyrimidines, Si306 and Pro-Si306, Inhibit Focal Adhesion Kinase and Suppress Human Glioblastoma Invasion In Vitro and In Vivo. in Cancers (Basel). 2020;12(6):1570.
doi:10.3390/cancers12061570 .

Nešović, Marija, Divac Rankov, Aleksandra, Podolski-Renić, Ana, Nikolić, Igor, Tasić, Goran, Mancini, Arianna, Schenone, Silvia, Pešić, Milica, Dinić, Jelena, "Src Inhibitors Pyrazolo[3,4-d]pyrimidines, Si306 and Pro-Si306, Inhibit Focal Adhesion Kinase and Suppress Human Glioblastoma Invasion In Vitro and In Vivo" in Cancers (Basel), 12, no. 6 (2020):1570,
https://doi.org/10.3390/cancers12061570 . .

TY  - JOUR
AU  - Jovanović, Mirna
AU  - Zhukovsky, Daniil
AU  - Podolski-Renić, Ana
AU  - Žalubovskis, Raivis
AU  - Dar'in, Dmitry
AU  - Sharoyko, Vladimir
AU  - Tennikova, Tatiana
AU  - Pešić, Milica
AU  - Krasavin, Mikhail
PY  - 2020
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3614
AB  - A series of analogs of the earlier reported lead compound DVD-445 (thioredoxin reductase inhibitor with anticancer activity) has been synthesized via a modified Ugi reaction and investigated. Seven most potent compounds (with IC50 below 5.00 μM against recombinant rTrxR1 enzyme) were examined for their effect on cell growth and viability, oxidative stress induction and P-glycoprotein (P-gp) inhibition in human glioblastoma cells cell line U87 and its corresponding multidrug resistant (MDR) cell line U87-TxR. Several of these frontrunner compounds were shown to be superior over DVD-445. Besides providing promising candidates for anticancer therapy, our study further validates the small electrophilic Ugi Michael acceptor (UMA) chemotype as efficacious inhibitor of thioredoxin reductase.
T2  - European Journal of Medicinal Chemistry
T1  - Further exploration of DVD-445 as a lead thioredoxin reductase (TrxR) inhibitor for cancer therapy: Optimization of potency and evaluation of anticancer potential.
VL  - 191
DO  - 10.1016/j.ejmech.2020.112119
SP  - 112119
ER  - 

@article{
author = "Jovanović, Mirna and Zhukovsky, Daniil and Podolski-Renić, Ana and Žalubovskis, Raivis and Dar'in, Dmitry and Sharoyko, Vladimir and Tennikova, Tatiana and Pešić, Milica and Krasavin, Mikhail",
year = "2020",
abstract = "A series of analogs of the earlier reported lead compound DVD-445 (thioredoxin reductase inhibitor with anticancer activity) has been synthesized via a modified Ugi reaction and investigated. Seven most potent compounds (with IC50 below 5.00 μM against recombinant rTrxR1 enzyme) were examined for their effect on cell growth and viability, oxidative stress induction and P-glycoprotein (P-gp) inhibition in human glioblastoma cells cell line U87 and its corresponding multidrug resistant (MDR) cell line U87-TxR. Several of these frontrunner compounds were shown to be superior over DVD-445. Besides providing promising candidates for anticancer therapy, our study further validates the small electrophilic Ugi Michael acceptor (UMA) chemotype as efficacious inhibitor of thioredoxin reductase.",
journal = "European Journal of Medicinal Chemistry",
title = "Further exploration of DVD-445 as a lead thioredoxin reductase (TrxR) inhibitor for cancer therapy: Optimization of potency and evaluation of anticancer potential.",
volume = "191",
doi = "10.1016/j.ejmech.2020.112119",
pages = "112119"
}

Jovanović, M., Zhukovsky, D., Podolski-Renić, A., Žalubovskis, R., Dar'in, D., Sharoyko, V., Tennikova, T., Pešić, M.,& Krasavin, M.. (2020). Further exploration of DVD-445 as a lead thioredoxin reductase (TrxR) inhibitor for cancer therapy: Optimization of potency and evaluation of anticancer potential.. in European Journal of Medicinal Chemistry, 191, 112119.
https://doi.org/10.1016/j.ejmech.2020.112119

Jovanović M, Zhukovsky D, Podolski-Renić A, Žalubovskis R, Dar'in D, Sharoyko V, Tennikova T, Pešić M, Krasavin M. Further exploration of DVD-445 as a lead thioredoxin reductase (TrxR) inhibitor for cancer therapy: Optimization of potency and evaluation of anticancer potential.. in European Journal of Medicinal Chemistry. 2020;191:112119.
doi:10.1016/j.ejmech.2020.112119 .

Jovanović, Mirna, Zhukovsky, Daniil, Podolski-Renić, Ana, Žalubovskis, Raivis, Dar'in, Dmitry, Sharoyko, Vladimir, Tennikova, Tatiana, Pešić, Milica, Krasavin, Mikhail, "Further exploration of DVD-445 as a lead thioredoxin reductase (TrxR) inhibitor for cancer therapy: Optimization of potency and evaluation of anticancer potential." in European Journal of Medicinal Chemistry, 191 (2020):112119,
https://doi.org/10.1016/j.ejmech.2020.112119 . .

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  - Musso, Loana
AU  - Dinić, Jelena
AU  - Podolski-Renić, Ana
AU  - Jovanović, Mirna
AU  - Dallavalle, Sabrina
AU  - Pešić, Milica
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6044
AB  - Cancer chemotherapy is often compromised by development of multidrug resistance (MDR). Numerous strategies have been developed over recent decades to overcome cancer resistance but this issue remains unsolved in clinical practice. Dual-targeting by a single drug emerged as an unconventional approach to overcome incomplete efficacy of individual targeting agents. Heat Shock Protein 90 (HSP90) chaperone interacts with a broad range of client proteins involved in cancerogenesis and cancer progression. Its overexpression was found in several cancer types and thus it is considered a valuable target for anticancer treatment. However, HSP90 inhibitors were unsuccessful in clinical studies due to high toxicity, lack of selectivity against cancer cells and extrusion by membrane transporters such as P-glycoprotein (P-gp). P-gp is responsible for low efficacy of anticancer drugs in more than 50% of cancers. Recognizing the potential of new compounds to inhibit P-gp function and/or expression is essential in the search for effective anticancer agents. We have synthesized 11 novel HSP90 inhibitors containing an
isoxazolonaphtoquinone core and identified candidates that inhibit P-gp and modulate MDR. HSP90 inhibitors were evaluated in MDR models comprised of sensitive and corresponding resistant cancer cells with P-gp overexpression (non-small cell lung carcinoma NCI-H460 and NCIH460/R; colorectal adenocarcinoma DLD1 and DLD1-TxR) as well as human normal embryonic fibroblasts MRC-5. We have investigated the effect of HSP90 inhibitors on cell growth inhibition, P-gp function, and P-gp mRNA and protein expression. Additionally, optimization of HSP90 inhibitors’ MDR modulation was performed by kinetics and dose response studies. Compounds 1 and 2 directly interacted with P-gp and
inhibited its activity. Similar cytotoxicity of 1 and 2 in sensitive and MDR cancer cells indicated these compounds are not P-gp substrates. On contrary, the effect of compound 3 was significantly reduced in MDR cancer cells, indicating that this compound acts as P-gp substrate, exerting competitive inhibitory effect on P-gp. Inhibition of P-gp activity after 1, 2 and 3 treatment lasted 24 h. These compounds also showed good relative selectivity towards cancer cells. Compound 4 had no direct effect on P-gp activity but significantly suppressed P-gp expression after 72 h treatment.
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  - Potential of novel Heat Shock Protein 90 (HSP90) inhibitors for P-glycoprotein inhibition and cancer multidrug resistance reversal
SP  - 30
EP  - 30
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6044
ER  - 

@conference{
author = "Musso, Loana and Dinić, Jelena and Podolski-Renić, Ana and Jovanović, Mirna and Dallavalle, Sabrina and Pešić, Milica",
year = "2019",
abstract = "Cancer chemotherapy is often compromised by development of multidrug resistance (MDR). Numerous strategies have been developed over recent decades to overcome cancer resistance but this issue remains unsolved in clinical practice. Dual-targeting by a single drug emerged as an unconventional approach to overcome incomplete efficacy of individual targeting agents. Heat Shock Protein 90 (HSP90) chaperone interacts with a broad range of client proteins involved in cancerogenesis and cancer progression. Its overexpression was found in several cancer types and thus it is considered a valuable target for anticancer treatment. However, HSP90 inhibitors were unsuccessful in clinical studies due to high toxicity, lack of selectivity against cancer cells and extrusion by membrane transporters such as P-glycoprotein (P-gp). P-gp is responsible for low efficacy of anticancer drugs in more than 50% of cancers. Recognizing the potential of new compounds to inhibit P-gp function and/or expression is essential in the search for effective anticancer agents. We have synthesized 11 novel HSP90 inhibitors containing an
isoxazolonaphtoquinone core and identified candidates that inhibit P-gp and modulate MDR. HSP90 inhibitors were evaluated in MDR models comprised of sensitive and corresponding resistant cancer cells with P-gp overexpression (non-small cell lung carcinoma NCI-H460 and NCIH460/R; colorectal adenocarcinoma DLD1 and DLD1-TxR) as well as human normal embryonic fibroblasts MRC-5. We have investigated the effect of HSP90 inhibitors on cell growth inhibition, P-gp function, and P-gp mRNA and protein expression. Additionally, optimization of HSP90 inhibitors’ MDR modulation was performed by kinetics and dose response studies. Compounds 1 and 2 directly interacted with P-gp and
inhibited its activity. Similar cytotoxicity of 1 and 2 in sensitive and MDR cancer cells indicated these compounds are not P-gp substrates. On contrary, the effect of compound 3 was significantly reduced in MDR cancer cells, indicating that this compound acts as P-gp substrate, exerting competitive inhibitory effect on P-gp. Inhibition of P-gp activity after 1, 2 and 3 treatment lasted 24 h. These compounds also showed good relative selectivity towards cancer cells. Compound 4 had no direct effect on P-gp activity but significantly suppressed P-gp expression after 72 h treatment.",
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 = "Potential of novel Heat Shock Protein 90 (HSP90) inhibitors for P-glycoprotein inhibition and cancer multidrug resistance reversal",
pages = "30-30",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6044"
}

Musso, L., Dinić, J., Podolski-Renić, A., Jovanović, M., Dallavalle, S.,& Pešić, M.. (2019). Potential of novel Heat Shock Protein 90 (HSP90) inhibitors for P-glycoprotein inhibition and cancer multidrug resistance reversal. 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., 30-30.
https://hdl.handle.net/21.15107/rcub_ibiss_6044

Musso L, Dinić J, Podolski-Renić A, Jovanović M, Dallavalle S, Pešić M. Potential of novel Heat Shock Protein 90 (HSP90) inhibitors for P-glycoprotein inhibition and cancer multidrug resistance reversal. 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;:30-30.
https://hdl.handle.net/21.15107/rcub_ibiss_6044 .

Musso, Loana, Dinić, Jelena, Podolski-Renić, Ana, Jovanović, Mirna, Dallavalle, Sabrina, Pešić, Milica, "Potential of novel Heat Shock Protein 90 (HSP90) inhibitors for P-glycoprotein inhibition and cancer multidrug resistance reversal" 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):30-30,
https://hdl.handle.net/21.15107/rcub_ibiss_6044 .

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  - Paskaš, Svetlana
AU  - Krajnović, Tamara
AU  - Basile, Maria S.
AU  - Dunđerović, Duško
AU  - Cavalli, Eugenio
AU  - Mangano, Katia
AU  - Mammana, Santa
AU  - Al-Abed, Yousef
AU  - Nicoletti, Ferdinando
AU  - Mijatović, Sanja
AU  - Maksimović-Ivanić, Danijela
PY  - 2019
UR  - https://onlinelibrary.wiley.com/doi/abs/10.1002/mc.23020
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3339
AB  - The main focus of this study is exploring the effect and mechanism of two HIV-protease inhibitors: Ritonavir and Ritonavir-nitric oxide (Ritonavir-NO) on in vitro growth of melanoma cell lines. NO modification significantly improved the antitumor potential of Ritonavir, as the IC50 values of Ritonavir-NO were approximately two times lower than IC50 values of the parental compound. Our results showed for the first time, that both compounds induced senescence in primary and metastatic melanoma cell lines. This transformation was manifested as a change in cell morphology, enlargement of nuclei, increased cellular granulation, upregulation of β-galactosidase activity, lipofuscin granules appearance, higher production of reactive oxygen species and persistent inhibition of proliferation. The expression of p53, as one of the key regulators of senescence, was upregulated after 48 hours of Ritonavir-NO treatment only in metastatic B16F10 cells, ranking it as a late-response event. The development of senescent phenotype was consistent with the alteration of the cytoskeleton-as we observed diminished expression of vinculin, α-actin, and β-tubulin. Permanent inhibition of S6 protein by Ritonavir-NO, but not Ritonavir, could be responsible for a stronger antiproliferative potential of the NO-modified compound. Taken together, induction of senescent phenotype may provide an excellent platform for developing therapeutic approaches based on selective killing of senescent cells.
T2  - Molecular Carcinogenesis
T2  - Molecular Carcinogenesis
T1  - Senescence as a main mechanism of Ritonavir and Ritonavir-NO action against melanoma.
DO  - 10.1002/mc.23020
ER  - 

@article{
author = "Paskaš, Svetlana and Krajnović, Tamara and Basile, Maria S. and Dunđerović, Duško and Cavalli, Eugenio and Mangano, Katia and Mammana, Santa and Al-Abed, Yousef and Nicoletti, Ferdinando and Mijatović, Sanja and Maksimović-Ivanić, Danijela",
year = "2019",
abstract = "The main focus of this study is exploring the effect and mechanism of two HIV-protease inhibitors: Ritonavir and Ritonavir-nitric oxide (Ritonavir-NO) on in vitro growth of melanoma cell lines. NO modification significantly improved the antitumor potential of Ritonavir, as the IC50 values of Ritonavir-NO were approximately two times lower than IC50 values of the parental compound. Our results showed for the first time, that both compounds induced senescence in primary and metastatic melanoma cell lines. This transformation was manifested as a change in cell morphology, enlargement of nuclei, increased cellular granulation, upregulation of β-galactosidase activity, lipofuscin granules appearance, higher production of reactive oxygen species and persistent inhibition of proliferation. The expression of p53, as one of the key regulators of senescence, was upregulated after 48 hours of Ritonavir-NO treatment only in metastatic B16F10 cells, ranking it as a late-response event. The development of senescent phenotype was consistent with the alteration of the cytoskeleton-as we observed diminished expression of vinculin, α-actin, and β-tubulin. Permanent inhibition of S6 protein by Ritonavir-NO, but not Ritonavir, could be responsible for a stronger antiproliferative potential of the NO-modified compound. Taken together, induction of senescent phenotype may provide an excellent platform for developing therapeutic approaches based on selective killing of senescent cells.",
journal = "Molecular Carcinogenesis, Molecular Carcinogenesis",
title = "Senescence as a main mechanism of Ritonavir and Ritonavir-NO action against melanoma.",
doi = "10.1002/mc.23020"
}

Paskaš, S., Krajnović, T., Basile, M. S., Dunđerović, D., Cavalli, E., Mangano, K., Mammana, S., Al-Abed, Y., Nicoletti, F., Mijatović, S.,& Maksimović-Ivanić, D.. (2019). Senescence as a main mechanism of Ritonavir and Ritonavir-NO action against melanoma.. in Molecular Carcinogenesis.
https://doi.org/10.1002/mc.23020

Paskaš S, Krajnović T, Basile MS, Dunđerović D, Cavalli E, Mangano K, Mammana S, Al-Abed Y, Nicoletti F, Mijatović S, Maksimović-Ivanić D. Senescence as a main mechanism of Ritonavir and Ritonavir-NO action against melanoma.. in Molecular Carcinogenesis. 2019;.
doi:10.1002/mc.23020 .

Paskaš, Svetlana, Krajnović, Tamara, Basile, Maria S., Dunđerović, Duško, Cavalli, Eugenio, Mangano, Katia, Mammana, Santa, Al-Abed, Yousef, Nicoletti, Ferdinando, Mijatović, Sanja, Maksimović-Ivanić, Danijela, "Senescence as a main mechanism of Ritonavir and Ritonavir-NO action against melanoma." in Molecular Carcinogenesis (2019),
https://doi.org/10.1002/mc.23020 . .

TY  - JOUR
AU  - Alexa-Stratulat, Teodora
AU  - Pešić, Milica
AU  - Čipak Gašparović, Ana
AU  - Trougakos, Ioannis
AU  - Riganti, Chiara
PY  - 2019
UR  - https://www.sciencedirect.com/science/article/pii/S1368764619300329?via%3Dihub
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4642
AB  - Identification of multidrug (MDR) efflux transporters that belong to the ATP-Binding Cassette (ABC) superfamily, represented an important breakthrough for understanding cancer multidrug resistance (MDR) and its possible overcoming. However, recent data indicate that drug resistant cells have a complex intracellular physiology that involves constant changes in energetic and oxidative-reductive metabolic pathways, as well as in the molecular circuitries connecting mitochondria, endoplasmic reticulum (ER) and lysosomes. The aim of this review is to discuss the key molecular mechanisms of cellular reprogramming that induce and maintain MDR, beyond the presence of MDR efflux transporters. We specifically highlight how cancer cells characterized by high metabolic plasticity – i.e. cells able to shift the energy metabolism between glycolysis and oxidative phosphorylation, to survive both the normoxic and hypoxic conditions, to modify the cytosolic and mitochondrial oxidative-reductive metabolism, are more prone to adapt to exogenous stressors such as anti-cancer drugs and acquire a MDR phenotype. Similarly, we discuss how changes in mitochondria dynamics and mitophagy rates, changes in proteome stability ensuring non-oncogenic proteostatic mechanisms, changes in ubiquitin/proteasome- and autophagy/lysosome-related pathways, promote the cellular survival under stress conditions, along with the acquisition or maintenance of MDR.
After dissecting the complex intracellular crosstalk that takes place during the development of MDR, we suggest that mapping the specific adaptation pathways underlying cell survival in response to stress and targeting these pathways with potent pharmacologic agents may be a new approach to enhance therapeutic efficacy against MDR tumors.
PB  - Amsterdam : Elsevier Ltd
T2  - Drug Resistance Updates
T1  - What sustains the multidrug resistance phenotype beyond ABC efflux transporters? Looking beyond the tip of the iceberg
VL  - 46
DO  - 10.1016/j.drup.2019.100643
SP  - 100643
ER  - 

@article{
author = "Alexa-Stratulat, Teodora and Pešić, Milica and Čipak Gašparović, Ana and Trougakos, Ioannis and Riganti, Chiara",
year = "2019",
abstract = "Identification of multidrug (MDR) efflux transporters that belong to the ATP-Binding Cassette (ABC) superfamily, represented an important breakthrough for understanding cancer multidrug resistance (MDR) and its possible overcoming. However, recent data indicate that drug resistant cells have a complex intracellular physiology that involves constant changes in energetic and oxidative-reductive metabolic pathways, as well as in the molecular circuitries connecting mitochondria, endoplasmic reticulum (ER) and lysosomes. The aim of this review is to discuss the key molecular mechanisms of cellular reprogramming that induce and maintain MDR, beyond the presence of MDR efflux transporters. We specifically highlight how cancer cells characterized by high metabolic plasticity – i.e. cells able to shift the energy metabolism between glycolysis and oxidative phosphorylation, to survive both the normoxic and hypoxic conditions, to modify the cytosolic and mitochondrial oxidative-reductive metabolism, are more prone to adapt to exogenous stressors such as anti-cancer drugs and acquire a MDR phenotype. Similarly, we discuss how changes in mitochondria dynamics and mitophagy rates, changes in proteome stability ensuring non-oncogenic proteostatic mechanisms, changes in ubiquitin/proteasome- and autophagy/lysosome-related pathways, promote the cellular survival under stress conditions, along with the acquisition or maintenance of MDR.
After dissecting the complex intracellular crosstalk that takes place during the development of MDR, we suggest that mapping the specific adaptation pathways underlying cell survival in response to stress and targeting these pathways with potent pharmacologic agents may be a new approach to enhance therapeutic efficacy against MDR tumors.",
publisher = "Amsterdam : Elsevier Ltd",
journal = "Drug Resistance Updates",
title = "What sustains the multidrug resistance phenotype beyond ABC efflux transporters? Looking beyond the tip of the iceberg",
volume = "46",
doi = "10.1016/j.drup.2019.100643",
pages = "100643"
}

Alexa-Stratulat, T., Pešić, M., Čipak Gašparović, A., Trougakos, I.,& Riganti, C.. (2019). What sustains the multidrug resistance phenotype beyond ABC efflux transporters? Looking beyond the tip of the iceberg. in Drug Resistance Updates
Amsterdam : Elsevier Ltd., 46, 100643.
https://doi.org/10.1016/j.drup.2019.100643

Alexa-Stratulat T, Pešić M, Čipak Gašparović A, Trougakos I, Riganti C. What sustains the multidrug resistance phenotype beyond ABC efflux transporters? Looking beyond the tip of the iceberg. in Drug Resistance Updates. 2019;46:100643.
doi:10.1016/j.drup.2019.100643 .

Alexa-Stratulat, Teodora, Pešić, Milica, Čipak Gašparović, Ana, Trougakos, Ioannis, Riganti, Chiara, "What sustains the multidrug resistance phenotype beyond ABC efflux transporters? Looking beyond the tip of the iceberg" in Drug Resistance Updates, 46 (2019):100643,
https://doi.org/10.1016/j.drup.2019.100643 . .

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  - Paskaš, Svetlana
AU  - Krajnović, Tamara
AU  - Basile, Maria S.
AU  - Dunđerović, Duško
AU  - Cavalli, Eugenio
AU  - Mangano, Katia
AU  - Mammana, Sant
AU  - Al‐Abed, Yousef
AU  - Nicoletti, Ferdinando
AU  - Mijatović, Sanja
AU  - Maksimović-Ivanić, Danijela
PY  - 2019
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3780
AB  - The main focus of this study is exploring the effect and mechanism of two HIVprotease
inhibitors: Ritonavir and Ritonavir‐nitric oxide (Ritonavir‐NO) on in vitro
growth of melanoma cell lines. NO modification significantly improved the antitumor
potential of Ritonavir, as the IC50 values of Ritonavir‐NO were approximately two
times lower than IC50 values of the parental compound. Our results showed for the
first time, that both compounds induced senescence in primary and metastatic
melanoma cell lines. This transformation was manifested as a change in cell
morphology, enlargement of nuclei, increased cellular granulation, upregulation of
β‐galactosidase activity, lipofuscin granules appearance, higher production of reactive
oxygen species and persistent inhibition of proliferation. The expression of p53, as
one of the key regulators of senescence, was upregulated after 48 hours of Ritonavir‐
NO treatment only in metastatic B16F10 cells, ranking it as a late‐response event.
The development of senescent phenotype was consistent with the alteration of
the cytoskeleton—as we observed diminished expression of vinculin, α‐actin, and
β‐tubulin. Permanent inhibition of S6 protein by Ritonavir‐NO, but not Ritonavir,
could be responsible for a stronger antiproliferative potential of the NO‐modified
compound. Taken together, induction of senescent phenotype may provide an
excellent platform for developing therapeutic approaches based on selective killing of
senescent cells.
PB  - New Jersey: Wiley-VCH Verlag GmbH & Co
T2  - Molecular Carcinogenesis
T1  - Senescence as a main mechanism of Ritonavir and Ritonavir‐NO action against melanoma
IS  - 8
VL  - 58
DO  - 10.1002/mc.23020
SP  - 1362
EP  - 1375
ER  - 

@article{
author = "Paskaš, Svetlana and Krajnović, Tamara and Basile, Maria S. and Dunđerović, Duško and Cavalli, Eugenio and Mangano, Katia and Mammana, Sant and Al‐Abed, Yousef and Nicoletti, Ferdinando and Mijatović, Sanja and Maksimović-Ivanić, Danijela",
year = "2019",
abstract = "The main focus of this study is exploring the effect and mechanism of two HIVprotease
inhibitors: Ritonavir and Ritonavir‐nitric oxide (Ritonavir‐NO) on in vitro
growth of melanoma cell lines. NO modification significantly improved the antitumor
potential of Ritonavir, as the IC50 values of Ritonavir‐NO were approximately two
times lower than IC50 values of the parental compound. Our results showed for the
first time, that both compounds induced senescence in primary and metastatic
melanoma cell lines. This transformation was manifested as a change in cell
morphology, enlargement of nuclei, increased cellular granulation, upregulation of
β‐galactosidase activity, lipofuscin granules appearance, higher production of reactive
oxygen species and persistent inhibition of proliferation. The expression of p53, as
one of the key regulators of senescence, was upregulated after 48 hours of Ritonavir‐
NO treatment only in metastatic B16F10 cells, ranking it as a late‐response event.
The development of senescent phenotype was consistent with the alteration of
the cytoskeleton—as we observed diminished expression of vinculin, α‐actin, and
β‐tubulin. Permanent inhibition of S6 protein by Ritonavir‐NO, but not Ritonavir,
could be responsible for a stronger antiproliferative potential of the NO‐modified
compound. Taken together, induction of senescent phenotype may provide an
excellent platform for developing therapeutic approaches based on selective killing of
senescent cells.",
publisher = "New Jersey: Wiley-VCH Verlag GmbH & Co",
journal = "Molecular Carcinogenesis",
title = "Senescence as a main mechanism of Ritonavir and Ritonavir‐NO action against melanoma",
number = "8",
volume = "58",
doi = "10.1002/mc.23020",
pages = "1362-1375"
}

Paskaš, S., Krajnović, T., Basile, M. S., Dunđerović, D., Cavalli, E., Mangano, K., Mammana, S., Al‐Abed, Y., Nicoletti, F., Mijatović, S.,& Maksimović-Ivanić, D.. (2019). Senescence as a main mechanism of Ritonavir and Ritonavir‐NO action against melanoma. in Molecular Carcinogenesis
New Jersey: Wiley-VCH Verlag GmbH & Co., 58(8), 1362-1375.
https://doi.org/10.1002/mc.23020

Paskaš S, Krajnović T, Basile MS, Dunđerović D, Cavalli E, Mangano K, Mammana S, Al‐Abed Y, Nicoletti F, Mijatović S, Maksimović-Ivanić D. Senescence as a main mechanism of Ritonavir and Ritonavir‐NO action against melanoma. in Molecular Carcinogenesis. 2019;58(8):1362-1375.
doi:10.1002/mc.23020 .

Paskaš, Svetlana, Krajnović, Tamara, Basile, Maria S., Dunđerović, Duško, Cavalli, Eugenio, Mangano, Katia, Mammana, Sant, Al‐Abed, Yousef, Nicoletti, Ferdinando, Mijatović, Sanja, Maksimović-Ivanić, Danijela, "Senescence as a main mechanism of Ritonavir and Ritonavir‐NO action against melanoma" in Molecular Carcinogenesis, 58, no. 8 (2019):1362-1375,
https://doi.org/10.1002/mc.23020 . .

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  - Jovanović, Mirna
AU  - Zhukovsky, Daniil
AU  - Podolski-Renić, Ana
AU  - Domračeva, Ilona
AU  - Žalubovskis, Raivis
AU  - Senćanski, Milan
AU  - Glišić, Sanja
AU  - Sharoyko, Vladimir
AU  - Tennikova, Tatiana
AU  - Dar'in, Dmitry
AU  - Pešić, Milica
AU  - Krasavin, Mikhail
PY  - 2019
UR  - https://www.sciencedirect.com/science/article/pii/S0223523419307147?via%3Dihub
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3488
AB  - A series of peptidomimetic compounds incorporating an electrophilic moiety was synthesized using the Ugi reaction. These compounds (termed the Ugi Michael acceptors or UMAs) were designed to target the selenocysteine catalytic residue of thioredoxin reductase 1 (TrxR1), a promising cancer target. The compounds were assessed for their potential to inhibit TrxR1 using human neuroblastoma (SH-SY5Y) cell lysate. Based on this initial screening, six compounds were selected for testing against recombinant rat TrxR1 and in the insulin assay to reveal low-micromolar to submicromolar potency of these inhibitors. The same frontrunner compounds were evaluated for their ability to exert antiproliferative activity and induce cell death and this activity was compared to the UMA effects on the levels of reactive oxygen and nitrogen species (RONS). Collectively, the UMA compounds class presented itself as a rich source of leads for TrxR1 inhibitor discovery for anticancer application. Compound 7 (DVD-445) was nominated a lead for further optimization.
T2  - European Journal of Medicinal Chemistry
T1  - Novel electrophilic amides amenable by the Ugi reaction perturb thioredoxin system via thioredoxin reductase 1 (TrxR1) inhibition: Identification of DVD-445 as a new lead compound for anticancer therapy.
VL  - 181
DO  - 10.1016/j.ejmech.2019.111580
SP  - 111580
ER  - 

@article{
author = "Jovanović, Mirna and Zhukovsky, Daniil and Podolski-Renić, Ana and Domračeva, Ilona and Žalubovskis, Raivis and Senćanski, Milan and Glišić, Sanja and Sharoyko, Vladimir and Tennikova, Tatiana and Dar'in, Dmitry and Pešić, Milica and Krasavin, Mikhail",
year = "2019",
abstract = "A series of peptidomimetic compounds incorporating an electrophilic moiety was synthesized using the Ugi reaction. These compounds (termed the Ugi Michael acceptors or UMAs) were designed to target the selenocysteine catalytic residue of thioredoxin reductase 1 (TrxR1), a promising cancer target. The compounds were assessed for their potential to inhibit TrxR1 using human neuroblastoma (SH-SY5Y) cell lysate. Based on this initial screening, six compounds were selected for testing against recombinant rat TrxR1 and in the insulin assay to reveal low-micromolar to submicromolar potency of these inhibitors. The same frontrunner compounds were evaluated for their ability to exert antiproliferative activity and induce cell death and this activity was compared to the UMA effects on the levels of reactive oxygen and nitrogen species (RONS). Collectively, the UMA compounds class presented itself as a rich source of leads for TrxR1 inhibitor discovery for anticancer application. Compound 7 (DVD-445) was nominated a lead for further optimization.",
journal = "European Journal of Medicinal Chemistry",
title = "Novel electrophilic amides amenable by the Ugi reaction perturb thioredoxin system via thioredoxin reductase 1 (TrxR1) inhibition: Identification of DVD-445 as a new lead compound for anticancer therapy.",
volume = "181",
doi = "10.1016/j.ejmech.2019.111580",
pages = "111580"
}

Jovanović, M., Zhukovsky, D., Podolski-Renić, A., Domračeva, I., Žalubovskis, R., Senćanski, M., Glišić, S., Sharoyko, V., Tennikova, T., Dar'in, D., Pešić, M.,& Krasavin, M.. (2019). Novel electrophilic amides amenable by the Ugi reaction perturb thioredoxin system via thioredoxin reductase 1 (TrxR1) inhibition: Identification of DVD-445 as a new lead compound for anticancer therapy.. in European Journal of Medicinal Chemistry, 181, 111580.
https://doi.org/10.1016/j.ejmech.2019.111580

Jovanović M, Zhukovsky D, Podolski-Renić A, Domračeva I, Žalubovskis R, Senćanski M, Glišić S, Sharoyko V, Tennikova T, Dar'in D, Pešić M, Krasavin M. Novel electrophilic amides amenable by the Ugi reaction perturb thioredoxin system via thioredoxin reductase 1 (TrxR1) inhibition: Identification of DVD-445 as a new lead compound for anticancer therapy.. in European Journal of Medicinal Chemistry. 2019;181:111580.
doi:10.1016/j.ejmech.2019.111580 .

Jovanović, Mirna, Zhukovsky, Daniil, Podolski-Renić, Ana, Domračeva, Ilona, Žalubovskis, Raivis, Senćanski, Milan, Glišić, Sanja, Sharoyko, Vladimir, Tennikova, Tatiana, Dar'in, Dmitry, Pešić, Milica, Krasavin, Mikhail, "Novel electrophilic amides amenable by the Ugi reaction perturb thioredoxin system via thioredoxin reductase 1 (TrxR1) inhibition: Identification of DVD-445 as a new lead compound for anticancer therapy." in European Journal of Medicinal Chemistry, 181 (2019):111580,
https://doi.org/10.1016/j.ejmech.2019.111580 . .

TY  - JOUR
AU  - Dinić, Jelena
AU  - Podolski-Renić, Ana
AU  - Jovanović, Mirna
AU  - Musso, Loana
AU  - Tsakovska, Ivanka
AU  - Pajeva, Ilza
AU  - Dallavalle, Sabrina
AU  - Pešić, Milica
PY  - 2019
UR  - https://www.mdpi.com/1422-0067/20/18/4575
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3476
AB  - Heat Shock Protein 90 (Hsp90) chaperone interacts with a broad range of client proteins involved in cancerogenesis and cancer progression. However, Hsp90 inhibitors were unsuccessful as anticancer agents due to their high toxicity, lack of selectivity against cancer cells and extrusion by membrane transporters responsible for multidrug resistance (MDR) such as P-glycoprotein (P-gp). Recognizing the potential of new compounds to inhibit P-gp function and/or expression is essential in the search for effective anticancer drugs. Eleven Hsp90 inhibitors containing an isoxazolonaphtoquinone core were synthesized and evaluated in two MDR models comprised of sensitive and corresponding resistant cancer cells with P-gp overexpression (human non-small cell lung carcinoma and colorectal adenocarcinoma). We investigated the effect of Hsp90 inhibitors on cell growth inhibition, P-gp activity and P-gp expression. Structure-activity relationship analysis was performed in respect to cell growth and P-gp inhibition. Compounds 5, 7, and 9 directly interacted with P-gp and inhibited its ATPase activity. Their potential P-gp binding site was identified by molecular docking studies. In addition, these compounds downregulated P-gp expression in MDR colorectal carcinoma cells, showed good relative selectivity towards cancer cells, while compound 5 reversed resistance to doxorubicin and paclitaxel in concentration-dependent manner. Therefore, compounds 5, 7 and 9 could be promising candidates for treating cancers with P-gp overexpression.
T2  - International Journal of Molecular Sciences
T1  - Novel Heat Shock Protein 90 Inhibitors Suppress P-Glycoprotein Activity and Overcome Multidrug Resistance in Cancer Cells.
IS  - 18
VL  - 20
DO  - 10.3390/ijms20184575
SP  - 4575
ER  - 

@article{
author = "Dinić, Jelena and Podolski-Renić, Ana and Jovanović, Mirna and Musso, Loana and Tsakovska, Ivanka and Pajeva, Ilza and Dallavalle, Sabrina and Pešić, Milica",
year = "2019",
abstract = "Heat Shock Protein 90 (Hsp90) chaperone interacts with a broad range of client proteins involved in cancerogenesis and cancer progression. However, Hsp90 inhibitors were unsuccessful as anticancer agents due to their high toxicity, lack of selectivity against cancer cells and extrusion by membrane transporters responsible for multidrug resistance (MDR) such as P-glycoprotein (P-gp). Recognizing the potential of new compounds to inhibit P-gp function and/or expression is essential in the search for effective anticancer drugs. Eleven Hsp90 inhibitors containing an isoxazolonaphtoquinone core were synthesized and evaluated in two MDR models comprised of sensitive and corresponding resistant cancer cells with P-gp overexpression (human non-small cell lung carcinoma and colorectal adenocarcinoma). We investigated the effect of Hsp90 inhibitors on cell growth inhibition, P-gp activity and P-gp expression. Structure-activity relationship analysis was performed in respect to cell growth and P-gp inhibition. Compounds 5, 7, and 9 directly interacted with P-gp and inhibited its ATPase activity. Their potential P-gp binding site was identified by molecular docking studies. In addition, these compounds downregulated P-gp expression in MDR colorectal carcinoma cells, showed good relative selectivity towards cancer cells, while compound 5 reversed resistance to doxorubicin and paclitaxel in concentration-dependent manner. Therefore, compounds 5, 7 and 9 could be promising candidates for treating cancers with P-gp overexpression.",
journal = "International Journal of Molecular Sciences",
title = "Novel Heat Shock Protein 90 Inhibitors Suppress P-Glycoprotein Activity and Overcome Multidrug Resistance in Cancer Cells.",
number = "18",
volume = "20",
doi = "10.3390/ijms20184575",
pages = "4575"
}

Dinić, J., Podolski-Renić, A., Jovanović, M., Musso, L., Tsakovska, I., Pajeva, I., Dallavalle, S.,& Pešić, M.. (2019). Novel Heat Shock Protein 90 Inhibitors Suppress P-Glycoprotein Activity and Overcome Multidrug Resistance in Cancer Cells.. in International Journal of Molecular Sciences, 20(18), 4575.
https://doi.org/10.3390/ijms20184575

Dinić J, Podolski-Renić A, Jovanović M, Musso L, Tsakovska I, Pajeva I, Dallavalle S, Pešić M. Novel Heat Shock Protein 90 Inhibitors Suppress P-Glycoprotein Activity and Overcome Multidrug Resistance in Cancer Cells.. in International Journal of Molecular Sciences. 2019;20(18):4575.
doi:10.3390/ijms20184575 .

Dinić, Jelena, Podolski-Renić, Ana, Jovanović, Mirna, Musso, Loana, Tsakovska, Ivanka, Pajeva, Ilza, Dallavalle, Sabrina, Pešić, Milica, "Novel Heat Shock Protein 90 Inhibitors Suppress P-Glycoprotein Activity and Overcome Multidrug Resistance in Cancer Cells." in International Journal of Molecular Sciences, 20, no. 18 (2019):4575,
https://doi.org/10.3390/ijms20184575 . .

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 . .