TY  - CONF
AU  - Jovanović, Mirna
AU  - Dragoj, Miodrag
AU  - Jovanović Stojanov, Sofija
AU  - Stepanović, Ana
AU  - Dinić, Jelena
AU  - Nešović, Marija
AU  - Pešić, Milica
AU  - Podolski-Renić, Ana
PY  - 2021
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/4867
AB  - Glioblastoma is the most frequent malignant brain tumor, with limited therapy options due to aggressive invasiveness and resistance to therapy . Elevated expression of redox system components, thioredoxin (Trx) and thioredoxin reductase (TrxR), is a common feature of cancer cells and correlates with cancer progression and poor prognosis. Therefore, Trx and TrxR are attractive targets for chemotherapy development. Inhibition of Trx system may also affect another important redox system – the glutathione (GSH) system. Here, we investigated weather GSH system can compensate Trx system inhibition by novel TrxR1 inhibitor (DVD-444) in human and rat drug resistant glioma cell lines and their sensitive counterparts. RT-qPCR analysis showed that DVD-444 decreased GSH peroxidase 1 (GPX1) and 4 (GPX4) mRNA expression in all glioma cell lines. Decrease in GPX expression indicates suppression of another antioxidant defense system, besides Trx system, leaving cells vulnerable to oxidative stress. Tested compound caused an increase in expression of GSH reductase (GR) and GSH-S transferase π (GSTπ). The observed increase in GR could be the consequence of oxidative stress imposed by treatment with TrxR1inhibitor, while elevated GSTπ implies that GSTπ is highly involved in detoxification of the applied compound. Furthermore, colorimetric GSH assay showed that DVD-444 increased GSH cell content in glioma cell lines. AV/PI staining following treatment with TrxR1 inhibitor demonstrated significant level of cell death in rat glioma cell lines. Based on CFSE staining DVD-444 showed antiproliferative effect in human glioma cells. In conclusion, TrxR1 inhibitor caused changes in components of GSH system. However, the changes in GSH system did not prevent inhibition of cell proliferation and cell death evasion after TrxR1 inhibition, making DVD-444 perspective candidate for glioblastoma treatment strategy
PB  - Elsevier Inc.
C3  - Free Radical Research Europe (SFRR-E) Annual Meeting Abstracts “Redox biology in the 21st century: a new scientific discipline” 15-18 June 2021, Belgrade, Serbia
T1  - Novel anti-cancer compound – inibitor of TrxR distress GSH system in glioma cells
DO  - 10.1016/j.freeradbiomed.2021.08.137
SP  - S97
ER  - 

@conference{
author = "Jovanović, Mirna and Dragoj, Miodrag and Jovanović Stojanov, Sofija and Stepanović, Ana and Dinić, Jelena and Nešović, Marija and Pešić, Milica and Podolski-Renić, Ana",
year = "2021",
abstract = "Glioblastoma is the most frequent malignant brain tumor, with limited therapy options due to aggressive invasiveness and resistance to therapy . Elevated expression of redox system components, thioredoxin (Trx) and thioredoxin reductase (TrxR), is a common feature of cancer cells and correlates with cancer progression and poor prognosis. Therefore, Trx and TrxR are attractive targets for chemotherapy development. Inhibition of Trx system may also affect another important redox system – the glutathione (GSH) system. Here, we investigated weather GSH system can compensate Trx system inhibition by novel TrxR1 inhibitor (DVD-444) in human and rat drug resistant glioma cell lines and their sensitive counterparts. RT-qPCR analysis showed that DVD-444 decreased GSH peroxidase 1 (GPX1) and 4 (GPX4) mRNA expression in all glioma cell lines. Decrease in GPX expression indicates suppression of another antioxidant defense system, besides Trx system, leaving cells vulnerable to oxidative stress. Tested compound caused an increase in expression of GSH reductase (GR) and GSH-S transferase π (GSTπ). The observed increase in GR could be the consequence of oxidative stress imposed by treatment with TrxR1inhibitor, while elevated GSTπ implies that GSTπ is highly involved in detoxification of the applied compound. Furthermore, colorimetric GSH assay showed that DVD-444 increased GSH cell content in glioma cell lines. AV/PI staining following treatment with TrxR1 inhibitor demonstrated significant level of cell death in rat glioma cell lines. Based on CFSE staining DVD-444 showed antiproliferative effect in human glioma cells. In conclusion, TrxR1 inhibitor caused changes in components of GSH system. However, the changes in GSH system did not prevent inhibition of cell proliferation and cell death evasion after TrxR1 inhibition, making DVD-444 perspective candidate for glioblastoma treatment strategy",
publisher = "Elsevier Inc.",
journal = "Free Radical Research Europe (SFRR-E) Annual Meeting Abstracts “Redox biology in the 21st century: a new scientific discipline” 15-18 June 2021, Belgrade, Serbia",
title = "Novel anti-cancer compound – inibitor of TrxR distress GSH system in glioma cells",
doi = "10.1016/j.freeradbiomed.2021.08.137",
pages = "S97"
}

Jovanović, M., Dragoj, M., Jovanović Stojanov, S., Stepanović, A., Dinić, J., Nešović, M., Pešić, M.,& Podolski-Renić, A.. (2021). Novel anti-cancer compound – inibitor of TrxR distress GSH system in glioma cells. in Free Radical Research Europe (SFRR-E) Annual Meeting Abstracts “Redox biology in the 21st century: a new scientific discipline” 15-18 June 2021, Belgrade, Serbia
Elsevier Inc.., S97.
https://doi.org/10.1016/j.freeradbiomed.2021.08.137

Jovanović M, Dragoj M, Jovanović Stojanov S, Stepanović A, Dinić J, Nešović M, Pešić M, Podolski-Renić A. Novel anti-cancer compound – inibitor of TrxR distress GSH system in glioma cells. in Free Radical Research Europe (SFRR-E) Annual Meeting Abstracts “Redox biology in the 21st century: a new scientific discipline” 15-18 June 2021, Belgrade, Serbia. 2021;:S97.
doi:10.1016/j.freeradbiomed.2021.08.137 .

Jovanović, Mirna, Dragoj, Miodrag, Jovanović Stojanov, Sofija, Stepanović, Ana, Dinić, Jelena, Nešović, Marija, Pešić, Milica, Podolski-Renić, Ana, "Novel anti-cancer compound – inibitor of TrxR distress GSH system in glioma cells" in Free Radical Research Europe (SFRR-E) Annual Meeting Abstracts “Redox biology in the 21st century: a new scientific discipline” 15-18 June 2021, Belgrade, Serbia (2021):S97,
https://doi.org/10.1016/j.freeradbiomed.2021.08.137 . .

TY  - CONF
AU  - Stepanović, Ana
AU  - Podolski-Renić, Ana
AU  - Jovanović Stojanov, Sofija
AU  - Nešović, Marija
AU  - Dragoj, Miodrag
AU  - Jovanović, Mirna
AU  - Nikolić, Igor
AU  - Tasić, Goran
AU  - Schenone, Silvia
AU  - Pešić, Milica
AU  - Dinić, Jelena
PY  - 2021
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/4801
AB  - Glioblastoma is the most frequent and aggressive brain tumor in adults. The main characteristics of glioblastoma include high proliferation rate, infiltrating nature, and resistance to chemotherapy and radiation. Glioblastoma cells highly express Src tyrosine kinase which has a key role in regulating survival, proliferation, angiogenesis and invasiveness of tumor cells. This tyrosine kinase is also an important regulator of reactive oxygen species production and cellular homeostasis. Anticancer properties of two pyrazolo[3,4-d]pyrimidine derivatives and Src tyrosine kinase inhibitors, Si306 and its prodrug pro-Si306, were investigated in human glioblastoma cell line U87, its multidrug-resistant (MDR) counterpart U87-TxR, and patient-derived glioblastoma cell culture. Si306 and pro-Si306 triggered reactive oxygen species and reactive nitrogen species production in sensitive and MDR glioblastoma cell lines and primary glioblastoma cells as evidenced by elevated levels of superoxide anion, hydrogen peroxide and peroxynitrite anion. Additionally, western blot analysis revealed elevated expression of superoxide dismutase 1, superoxide dismutase 2, and thioredoxin reductase 1 in glioblastoma cells after Si306 and pro-Si306 treatments. The levels of phosphorylated histone H2A.X increased in all glioblastoma cells after treatments with these inhibitors, demonstrating DNA damage. Both compounds also induced significant cell death in primary glioblastoma culture. In addition, the Src tyrosine kinase inhibitors prompted primary glioblastoma cells to enter senescence. The presence of the MDR phenotype did not reduce the activity of the compounds. Overall, the investigated pyrazolo[3,4-d]pyrimidines displayed significant anti-glioblastoma effects making them good candidates for further development as anticancer agents
PB  - Elsevier Inc.
C3  - Free Radical Research Europe (SFRR-E) Annual Meeting Abstracts “Redox biology in the 21st century: a new scientific discipline” 15-18 June 2021, Belgrade, Serbia
T1  - Pyrazolo[3,4-d]pyrimidine derivatives, Si306 and pro-Si306, induce oxidative stress and cell death in patient-derived glioblastoma cells
DO  - 10.1016/j.freeradbiomed.2021.08.082
SP  - S75
ER  - 

@conference{
author = "Stepanović, Ana and Podolski-Renić, Ana and Jovanović Stojanov, Sofija and Nešović, Marija and Dragoj, Miodrag and Jovanović, Mirna and Nikolić, Igor and Tasić, Goran and Schenone, Silvia and Pešić, Milica and Dinić, Jelena",
year = "2021",
abstract = "Glioblastoma is the most frequent and aggressive brain tumor in adults. The main characteristics of glioblastoma include high proliferation rate, infiltrating nature, and resistance to chemotherapy and radiation. Glioblastoma cells highly express Src tyrosine kinase which has a key role in regulating survival, proliferation, angiogenesis and invasiveness of tumor cells. This tyrosine kinase is also an important regulator of reactive oxygen species production and cellular homeostasis. Anticancer properties of two pyrazolo[3,4-d]pyrimidine derivatives and Src tyrosine kinase inhibitors, Si306 and its prodrug pro-Si306, were investigated in human glioblastoma cell line U87, its multidrug-resistant (MDR) counterpart U87-TxR, and patient-derived glioblastoma cell culture. Si306 and pro-Si306 triggered reactive oxygen species and reactive nitrogen species production in sensitive and MDR glioblastoma cell lines and primary glioblastoma cells as evidenced by elevated levels of superoxide anion, hydrogen peroxide and peroxynitrite anion. Additionally, western blot analysis revealed elevated expression of superoxide dismutase 1, superoxide dismutase 2, and thioredoxin reductase 1 in glioblastoma cells after Si306 and pro-Si306 treatments. The levels of phosphorylated histone H2A.X increased in all glioblastoma cells after treatments with these inhibitors, demonstrating DNA damage. Both compounds also induced significant cell death in primary glioblastoma culture. In addition, the Src tyrosine kinase inhibitors prompted primary glioblastoma cells to enter senescence. The presence of the MDR phenotype did not reduce the activity of the compounds. Overall, the investigated pyrazolo[3,4-d]pyrimidines displayed significant anti-glioblastoma effects making them good candidates for further development as anticancer agents",
publisher = "Elsevier Inc.",
journal = "Free Radical Research Europe (SFRR-E) Annual Meeting Abstracts “Redox biology in the 21st century: a new scientific discipline” 15-18 June 2021, Belgrade, Serbia",
title = "Pyrazolo[3,4-d]pyrimidine derivatives, Si306 and pro-Si306, induce oxidative stress and cell death in patient-derived glioblastoma cells",
doi = "10.1016/j.freeradbiomed.2021.08.082",
pages = "S75"
}

Stepanović, A., Podolski-Renić, A., Jovanović Stojanov, S., Nešović, M., Dragoj, M., Jovanović, M., Nikolić, I., Tasić, G., Schenone, S., Pešić, M.,& Dinić, J.. (2021). Pyrazolo[3,4-d]pyrimidine derivatives, Si306 and pro-Si306, induce oxidative stress and cell death in patient-derived glioblastoma cells. in Free Radical Research Europe (SFRR-E) Annual Meeting Abstracts “Redox biology in the 21st century: a new scientific discipline” 15-18 June 2021, Belgrade, Serbia
Elsevier Inc.., S75.
https://doi.org/10.1016/j.freeradbiomed.2021.08.082

Stepanović A, Podolski-Renić A, Jovanović Stojanov S, Nešović M, Dragoj M, Jovanović M, Nikolić I, Tasić G, Schenone S, Pešić M, Dinić J. Pyrazolo[3,4-d]pyrimidine derivatives, Si306 and pro-Si306, induce oxidative stress and cell death in patient-derived glioblastoma cells. in Free Radical Research Europe (SFRR-E) Annual Meeting Abstracts “Redox biology in the 21st century: a new scientific discipline” 15-18 June 2021, Belgrade, Serbia. 2021;:S75.
doi:10.1016/j.freeradbiomed.2021.08.082 .

Stepanović, Ana, Podolski-Renić, Ana, Jovanović Stojanov, Sofija, Nešović, Marija, Dragoj, Miodrag, Jovanović, Mirna, Nikolić, Igor, Tasić, Goran, Schenone, Silvia, Pešić, Milica, Dinić, Jelena, "Pyrazolo[3,4-d]pyrimidine derivatives, Si306 and pro-Si306, induce oxidative stress and cell death in patient-derived glioblastoma cells" in Free Radical Research Europe (SFRR-E) Annual Meeting Abstracts “Redox biology in the 21st century: a new scientific discipline” 15-18 June 2021, Belgrade, Serbia (2021):S75,
https://doi.org/10.1016/j.freeradbiomed.2021.08.082 . .

TY  - JOUR
AU  - Stepanović, Ana
AU  - Jovanović Stojanov, Sofija
AU  - Podolski-Renić, Ana
AU  - Nešović, Marija
AU  - Dragoj, Miodrag
AU  - Nikolić, Igor
AU  - Tasić, Goran
AU  - Schenone, Silvia
AU  - Pešić, Milica
AU  - Dinić, Jelena
PY  - 2021
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4258
AB  - Background: Glioblastoma (GBM) highly expresses Src tyrosine kinase involved in survival, proliferation, angiogenesis and invasiveness of tumor cells. Src activation also reduces reactive oxygen species (ROS) generation, whereas Src inhibitors are able to increase cellular ROS levels. Methods: Pro-oxidative effects of two pyrazolo[3,4-d]pyrimidine derivatives—Src tyrosine kinase inhibitors, Si306 and its prodrug pro-Si306—were investigated in human GBM cells U87 and patient-derived GBM-6. ROS production and changes in mitochondrial membrane potential were assessed by flow cytometry. The expression levels of superoxide dismutase 1 (SOD1) and 2 (SOD2) were studied by Western blot. DNA damage, cell death induction and senescence were also examined in GBM-6 cells. Results: Si306 and pro-Si306 more prominently triggered ROS production and expression of antioxidant enzymes in primary GBM cells. These effects were followed by mitochondrial membrane potential disruption, double-strand DNA breaks and senescence that eventually led to necrosis. Conclusion: Src kinase inhibitors, Si306 and pro-Si306, showed significant pro-oxidative potential in patient-derived GBM cells. This feature contributes to the already demonstrated anti-glioblastoma properties of these compounds in vitro and in vivo and encourages clinical investigations.
PB  - Basel : MDPI
T2  - Brain Sciences
T1  - Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors Induce Oxidative Stress in Patient-Derived Glioblastoma Cells
IS  - 7
VL  - 11
DO  - 10.3390/brainsci11070884
SP  - 884
ER  - 

@article{
author = "Stepanović, Ana and Jovanović Stojanov, Sofija and Podolski-Renić, Ana and Nešović, Marija and Dragoj, Miodrag and Nikolić, Igor and Tasić, Goran and Schenone, Silvia and Pešić, Milica and Dinić, Jelena",
year = "2021",
abstract = "Background: Glioblastoma (GBM) highly expresses Src tyrosine kinase involved in survival, proliferation, angiogenesis and invasiveness of tumor cells. Src activation also reduces reactive oxygen species (ROS) generation, whereas Src inhibitors are able to increase cellular ROS levels. Methods: Pro-oxidative effects of two pyrazolo[3,4-d]pyrimidine derivatives—Src tyrosine kinase inhibitors, Si306 and its prodrug pro-Si306—were investigated in human GBM cells U87 and patient-derived GBM-6. ROS production and changes in mitochondrial membrane potential were assessed by flow cytometry. The expression levels of superoxide dismutase 1 (SOD1) and 2 (SOD2) were studied by Western blot. DNA damage, cell death induction and senescence were also examined in GBM-6 cells. Results: Si306 and pro-Si306 more prominently triggered ROS production and expression of antioxidant enzymes in primary GBM cells. These effects were followed by mitochondrial membrane potential disruption, double-strand DNA breaks and senescence that eventually led to necrosis. Conclusion: Src kinase inhibitors, Si306 and pro-Si306, showed significant pro-oxidative potential in patient-derived GBM cells. This feature contributes to the already demonstrated anti-glioblastoma properties of these compounds in vitro and in vivo and encourages clinical investigations.",
publisher = "Basel : MDPI",
journal = "Brain Sciences",
title = "Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors Induce Oxidative Stress in Patient-Derived Glioblastoma Cells",
number = "7",
volume = "11",
doi = "10.3390/brainsci11070884",
pages = "884"
}

Stepanović, A., Jovanović Stojanov, S., Podolski-Renić, A., Nešović, M., Dragoj, M., Nikolić, I., Tasić, G., Schenone, S., Pešić, M.,& Dinić, J.. (2021). Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors Induce Oxidative Stress in Patient-Derived Glioblastoma Cells. in Brain Sciences
Basel : MDPI., 11(7), 884.
https://doi.org/10.3390/brainsci11070884

Stepanović A, Jovanović Stojanov S, Podolski-Renić A, Nešović M, Dragoj M, Nikolić I, Tasić G, Schenone S, Pešić M, Dinić J. Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors Induce Oxidative Stress in Patient-Derived Glioblastoma Cells. in Brain Sciences. 2021;11(7):884.
doi:10.3390/brainsci11070884 .

Stepanović, Ana, Jovanović Stojanov, Sofija, Podolski-Renić, Ana, Nešović, Marija, Dragoj, Miodrag, Nikolić, Igor, Tasić, Goran, Schenone, Silvia, Pešić, Milica, Dinić, Jelena, "Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors Induce Oxidative Stress in Patient-Derived Glioblastoma Cells" in Brain Sciences, 11, no. 7 (2021):884,
https://doi.org/10.3390/brainsci11070884 . .

TY  - THES
AU  - Nešović, Marija
PY  - 2021
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/4683
AB  - Glioblastomi su najagresivniji primarni tumora mozga, koje odlikuje visoka aktivnost Src tirozin-kinaze. Stoga, ovaj enzim, koji reguliše preživljavanje i invazivnost tumorskih ćelija, predstavlja potencijalnu metu za razvoj ciljane terapije. U ovom radu je ispitano dejstvo Src tirozin-kinaznih inhibitora, Si306 i njegovog proleka pro-Si306 na invazivni potencijal humanih ćelijskih linija glioblastoma (U87 i U87-TxR) i tri primarne ćelijske kulture glioblastoma, kao i na višestruku rezistenciju na lekove posredovanu ekspresijom P-glikoproteina u U87-TxR ćelijskoj liniji. P-glikoprotein je ATP vezujući transporter, koji ima protektivnu ulogu u krvno-moždanoj barijeri, dok na membrani tumorskih ćelija sprečava prodiranje brojnih lekova i tako umanjuje njihovu efikasnost. Značajan efekat Si306 i pro-Si306 na ćelijski rast glioblastoma dobijen je u mikromolarnom opsegu koncentracija 1-20 μM. Sposobnost ćelija glioblastoma da razgrade vanćelijski matriks je bila značajno smanjena primenom Src tirozin-kinaznih inhibitora. Oba inhibitora su uticala na ekspresiju komponenti Src signalnog puta i pokazala anti-invazivni potencijal in vitro. In vivo, inhibitori su sprečili invadiranje U87 ćelija u ksenograft modelu embriona zebrice. Pored svoje primarne uloge, Src tirozin-kinazni inhibitori su pokazali sposobnost da umanje aktivnost P-glikoproteina i povećaju efikasnost paklitaksela kod U87-TxR ćelija. Uzimajući u obzir rezultate ovog rada, Si306 i pro-Si306 predstavljaju kandidate za buduća klinička ispitivanja na glioblastomima kod kojih su terapeutske mogućnosti ograničene. Prolek pro-Si306 je pokazao sličnu efikasnost kao i Si306, što ukazuje na opravdanost njegove upotrebe zbog povoljnijih farmakokinetičkih svojstava u odnosu na sam lek.
AB  - Glioblastoma, as the most aggressive brain tumor, displays high activity of Src tyrosine kinase. Thus, this enzyme that participates in the survival, migration, and invasiveness of tumor cells emerged as a potential target for glioblastoma therapy. The effects of Src inhibitors, Si306 and its prodrug pro-Si306, on invasive potential in human glioblastoma cell lines (U87 and U87- TxR) and three primary glioblastoma cell cultures were investigated in this study. Another phenomenon investigated was multidrug resistance mediated by the overexpression of Pglycoprotein in the resistant glioblastoma cell line U87-TxR. This ATP-binding cassette membrane transporter has a protective role in the blood-brain barrier, while it limits drug delivery through tumor membrane and decreases their efficacy. Si306 and pro-Si306 have shown significant effects on cell growth of glioblastoma cells applied in concentrations range 1-20 μM. The ability of glioblastoma cells to degrade the extracellular matrix was considerably compromised after application of Src tyrosine kinase inhibitors. Both compounds affected Src signaling pathway members and showed their antiinvasive potential in vitro. In addition, Si306 and pro-Si306 displayed an anti-invasive effect against U87 xenografts in the zebrafish embryo model in vivo. Moreover, the tested compounds were found to inhibit the activity of P-glycoprotein, and enhance the efficacy of paclitaxel in Pglycoprotein overexpressing cells. Considering the results of this study, clinical testing of Si306 and pro-Si306 in glioblastoma with limited treatment options is anticipated in the near future. The prodrug showed similar efficacy to the drug, implying the rationality of its use in clinical settings.
PB  - Belgrade: Faculty of Biology, University of Belgrade
T2  - Faculty of Biology, University of Belgrade
T1  - Uloga inhibitora Src tirozin-kinaze u prevazilaženju urođeno rezistentnog i invazivnog fenotipa glioblastoma
T1  - The role of Src tyrosine kinase inhibitors in overcoming the intrinsically resistant and invasive phenotype of glioblastoma
SP  - 1
EP  - 85
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_4683
ER  - 

@phdthesis{
author = "Nešović, Marija",
year = "2021",
abstract = "Glioblastomi su najagresivniji primarni tumora mozga, koje odlikuje visoka aktivnost Src tirozin-kinaze. Stoga, ovaj enzim, koji reguliše preživljavanje i invazivnost tumorskih ćelija, predstavlja potencijalnu metu za razvoj ciljane terapije. U ovom radu je ispitano dejstvo Src tirozin-kinaznih inhibitora, Si306 i njegovog proleka pro-Si306 na invazivni potencijal humanih ćelijskih linija glioblastoma (U87 i U87-TxR) i tri primarne ćelijske kulture glioblastoma, kao i na višestruku rezistenciju na lekove posredovanu ekspresijom P-glikoproteina u U87-TxR ćelijskoj liniji. P-glikoprotein je ATP vezujući transporter, koji ima protektivnu ulogu u krvno-moždanoj barijeri, dok na membrani tumorskih ćelija sprečava prodiranje brojnih lekova i tako umanjuje njihovu efikasnost. Značajan efekat Si306 i pro-Si306 na ćelijski rast glioblastoma dobijen je u mikromolarnom opsegu koncentracija 1-20 μM. Sposobnost ćelija glioblastoma da razgrade vanćelijski matriks je bila značajno smanjena primenom Src tirozin-kinaznih inhibitora. Oba inhibitora su uticala na ekspresiju komponenti Src signalnog puta i pokazala anti-invazivni potencijal in vitro. In vivo, inhibitori su sprečili invadiranje U87 ćelija u ksenograft modelu embriona zebrice. Pored svoje primarne uloge, Src tirozin-kinazni inhibitori su pokazali sposobnost da umanje aktivnost P-glikoproteina i povećaju efikasnost paklitaksela kod U87-TxR ćelija. Uzimajući u obzir rezultate ovog rada, Si306 i pro-Si306 predstavljaju kandidate za buduća klinička ispitivanja na glioblastomima kod kojih su terapeutske mogućnosti ograničene. Prolek pro-Si306 je pokazao sličnu efikasnost kao i Si306, što ukazuje na opravdanost njegove upotrebe zbog povoljnijih farmakokinetičkih svojstava u odnosu na sam lek., Glioblastoma, as the most aggressive brain tumor, displays high activity of Src tyrosine kinase. Thus, this enzyme that participates in the survival, migration, and invasiveness of tumor cells emerged as a potential target for glioblastoma therapy. The effects of Src inhibitors, Si306 and its prodrug pro-Si306, on invasive potential in human glioblastoma cell lines (U87 and U87- TxR) and three primary glioblastoma cell cultures were investigated in this study. Another phenomenon investigated was multidrug resistance mediated by the overexpression of Pglycoprotein in the resistant glioblastoma cell line U87-TxR. This ATP-binding cassette membrane transporter has a protective role in the blood-brain barrier, while it limits drug delivery through tumor membrane and decreases their efficacy. Si306 and pro-Si306 have shown significant effects on cell growth of glioblastoma cells applied in concentrations range 1-20 μM. The ability of glioblastoma cells to degrade the extracellular matrix was considerably compromised after application of Src tyrosine kinase inhibitors. Both compounds affected Src signaling pathway members and showed their antiinvasive potential in vitro. In addition, Si306 and pro-Si306 displayed an anti-invasive effect against U87 xenografts in the zebrafish embryo model in vivo. Moreover, the tested compounds were found to inhibit the activity of P-glycoprotein, and enhance the efficacy of paclitaxel in Pglycoprotein overexpressing cells. Considering the results of this study, clinical testing of Si306 and pro-Si306 in glioblastoma with limited treatment options is anticipated in the near future. The prodrug showed similar efficacy to the drug, implying the rationality of its use in clinical settings.",
publisher = "Belgrade: Faculty of Biology, University of Belgrade",
journal = "Faculty of Biology, University of Belgrade",
title = "Uloga inhibitora Src tirozin-kinaze u prevazilaženju urođeno rezistentnog i invazivnog fenotipa glioblastoma, The role of Src tyrosine kinase inhibitors in overcoming the intrinsically resistant and invasive phenotype of glioblastoma",
pages = "1-85",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_4683"
}

Nešović, M.. (2021). Uloga inhibitora Src tirozin-kinaze u prevazilaženju urođeno rezistentnog i invazivnog fenotipa glioblastoma. in Faculty of Biology, University of Belgrade
Belgrade: Faculty of Biology, University of Belgrade., 1-85.
https://hdl.handle.net/21.15107/rcub_ibiss_4683

Nešović M. Uloga inhibitora Src tirozin-kinaze u prevazilaženju urođeno rezistentnog i invazivnog fenotipa glioblastoma. in Faculty of Biology, University of Belgrade. 2021;:1-85.
https://hdl.handle.net/21.15107/rcub_ibiss_4683 .

Nešović, Marija, "Uloga inhibitora Src tirozin-kinaze u prevazilaženju urođeno rezistentnog i invazivnog fenotipa glioblastoma" in Faculty of Biology, University of Belgrade (2021):1-85,
https://hdl.handle.net/21.15107/rcub_ibiss_4683 .

TY  - CONF
AU  - Dinić, Jelena
AU  - Podolski-Renić, Ana
AU  - Nešović, Marija
AU  - Stepanović, Ana
AU  - Divac Rankov, Aleksandra
AU  - Dragoj, Miodrag
AU  - Nikolić, Igor
AU  - Tasić, Goran
AU  - Pešić, Milica
PY  - 2020
UR  - https://stratagem-cost.eu/wp-content/uploads/2020/03/Abstract-book-Belgrade-2020.pdf
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5625
AB  - Glioblastoma (GBM) is the most frequent and aggressive brain tumor in adults. Main characteristics of GBM include high
proliferation rate, infiltrating nature, and resistance to chemotherapy and radiation. GBM have high expression of c-Src
tyrosine kinase which has a key role in regulating survival, proliferation, angiogenesis and invasiveness of tumor cells. Thus,
c-Src emerged as a potential target for GBM therapy. Anticancer properties of c-Src tyrosine kinase inhibitors Si306 and its
prodrug pro-Si306, pyrazolo[3,4-d]pyrimidines were assessed in human GBM cell line U87, its multidrug resistant (MDR)
counterpart U87-TxR, and human primary GBM culture. Si306 and pro-Si306 triggered ROS generation and DNA damage
in sensitive and MDR GBM cell lines, as well as primary GBM cells. Both compounds induced a prominent cell death in
primary GBM culture, while the effect on GBM cell lines was predominantly antiproliferative, characterized by decrease in
Ki-67 expression and cell cycle disturbance. Moreover, the investigated compounds made primary GBM culture more prone
to anoikis. In addition, Si306 and pro-Si306 showed strong antiproliferative effect in U87 xenografts in zebrafish embryo
model. The antiglioblastoma effects of investigated c-Src inhibitors were more prominent when compared to dasatinib, a
well-known tyrosine kinase inhibitor. The presence of the MDR phenotype did not diminish the activity of the compounds.
The investigated pyrazolo[3,4-d]pyrimidines displayed significant anticancer potential in GBM which makes them good
candidates for further development regarding treatment of this cancer type.
PB  - COST Action CA17104
C3  - Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug resistant tumours: Annual conference 3rd MC meeting and 4th WGs meeting; 2020 Feb 27-28; Belgrade, Serbia.
T1  - Pyrazolo[3,4-d]pyrimidine derivatives, Si306 and pro-Si306, inhibit the growth of sensitive and multidrug resistant glioblastoma
SP  - 35
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5625
ER  - 

@conference{
author = "Dinić, Jelena and Podolski-Renić, Ana and Nešović, Marija and Stepanović, Ana and Divac Rankov, Aleksandra and Dragoj, Miodrag and Nikolić, Igor and Tasić, Goran and Pešić, Milica",
year = "2020",
abstract = "Glioblastoma (GBM) is the most frequent and aggressive brain tumor in adults. Main characteristics of GBM include high
proliferation rate, infiltrating nature, and resistance to chemotherapy and radiation. GBM have high expression of c-Src
tyrosine kinase which has a key role in regulating survival, proliferation, angiogenesis and invasiveness of tumor cells. Thus,
c-Src emerged as a potential target for GBM therapy. Anticancer properties of c-Src tyrosine kinase inhibitors Si306 and its
prodrug pro-Si306, pyrazolo[3,4-d]pyrimidines were assessed in human GBM cell line U87, its multidrug resistant (MDR)
counterpart U87-TxR, and human primary GBM culture. Si306 and pro-Si306 triggered ROS generation and DNA damage
in sensitive and MDR GBM cell lines, as well as primary GBM cells. Both compounds induced a prominent cell death in
primary GBM culture, while the effect on GBM cell lines was predominantly antiproliferative, characterized by decrease in
Ki-67 expression and cell cycle disturbance. Moreover, the investigated compounds made primary GBM culture more prone
to anoikis. In addition, Si306 and pro-Si306 showed strong antiproliferative effect in U87 xenografts in zebrafish embryo
model. The antiglioblastoma effects of investigated c-Src inhibitors were more prominent when compared to dasatinib, a
well-known tyrosine kinase inhibitor. The presence of the MDR phenotype did not diminish the activity of the compounds.
The investigated pyrazolo[3,4-d]pyrimidines displayed significant anticancer potential in GBM which makes them good
candidates for further development regarding treatment of this cancer type.",
publisher = "COST Action CA17104",
journal = "Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug resistant tumours: Annual conference 3rd MC meeting and 4th WGs meeting; 2020 Feb 27-28; Belgrade, Serbia.",
title = "Pyrazolo[3,4-d]pyrimidine derivatives, Si306 and pro-Si306, inhibit the growth of sensitive and multidrug resistant glioblastoma",
pages = "35",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5625"
}

Dinić, J., Podolski-Renić, A., Nešović, M., Stepanović, A., Divac Rankov, A., Dragoj, M., Nikolić, I., Tasić, G.,& Pešić, M.. (2020). Pyrazolo[3,4-d]pyrimidine derivatives, Si306 and pro-Si306, inhibit the growth of sensitive and multidrug resistant glioblastoma. in Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug resistant tumours: Annual conference 3rd MC meeting and 4th WGs meeting; 2020 Feb 27-28; Belgrade, Serbia.
COST Action CA17104., 35.
https://hdl.handle.net/21.15107/rcub_ibiss_5625

Dinić J, Podolski-Renić A, Nešović M, Stepanović A, Divac Rankov A, Dragoj M, Nikolić I, Tasić G, Pešić M. Pyrazolo[3,4-d]pyrimidine derivatives, Si306 and pro-Si306, inhibit the growth of sensitive and multidrug resistant glioblastoma. in Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug resistant tumours: Annual conference 3rd MC meeting and 4th WGs meeting; 2020 Feb 27-28; Belgrade, Serbia.. 2020;:35.
https://hdl.handle.net/21.15107/rcub_ibiss_5625 .

Dinić, Jelena, Podolski-Renić, Ana, Nešović, Marija, Stepanović, Ana, Divac Rankov, Aleksandra, Dragoj, Miodrag, Nikolić, Igor, Tasić, Goran, Pešić, Milica, "Pyrazolo[3,4-d]pyrimidine derivatives, Si306 and pro-Si306, inhibit the growth of sensitive and multidrug resistant glioblastoma" in Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug resistant tumours: Annual conference 3rd MC meeting and 4th WGs meeting; 2020 Feb 27-28; Belgrade, Serbia. (2020):35,
https://hdl.handle.net/21.15107/rcub_ibiss_5625 .

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

TY  - JOUR
AU  - Milošević, Zorica
AU  - Banković, Jasna
AU  - Dinić, Jelena
AU  - Tsimplouli, Chrisiida
AU  - Sereti, Evangelia
AU  - Dragoj, Miodrag
AU  - Paunović, Verica
AU  - Milovanović, Zorka
AU  - Nešović, Marija
AU  - Tanić, Nikola
AU  - Dimas, Kostantinos
AU  - Pešić, Milica
PY  - 2018
UR  - https://link.springer.com/article/10.1007%2Fs13402-018-0380-x
UR  - https://radar.ibiss.bg.ac.rs/123456789/3887
AB  - Purpose: Anaplastic thyroid carcinoma (ATC) is an aggressive, chemo-resistant malignancy. Chemo-resistance is often associated with changes in activity of the RAS/MAPK/ERK and PI3K/AKT/mTOR pathways and/or a high expression of ATP binding cassette (ABC) transporters, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). To assess the therapeutic efficacy in ATC of a combination of the dual mTOR kinase inhibitor vistusertib (AZD2014) and paclitaxel (PTX), we generated a new cell line (Rho-) via the selection of human thyroid carcinoma 8505C cells that exhibit a low accumulation of rhodamine 123, which serves as a P-gp and BCRP substrate.
Methods: Immunohistochemistry was used for P-gp and BCRP expression analyses in primary ATC patient samples. Spheroid formation and immunodeficient NSG mice were used for performing in vitro and in vivo tumorigenicity assays, respectively. MTT, flow-cytometry, fluorescent microscopy, cell death and proliferation assays, as well as migration, invasion and gelatin degradation assays, were used to assess the potential of AZD2014 to enhance the effects of PTX. ATC xenografts in SCID mice were used for evaluating in vivo treatment efficacies.
Results: Rho- cells were found to be 10-fold more resistant to PTX than 8505C cells and, in addition, to be more tumorigenic. We also found that AZD2014 sensitized Rho- cells to PTX by inhibiting proliferation and by inducing autophagy. The combined use of AZD2014 and PTX efficiently inhibited in vitro ATC cell migration and invasion. Subsequent in vivo xenograft studies indicated that the AZD2014 and PTX combination effectively suppressed ATC tumor growth.
Conclusions: Our data support results from recent phase I clinical trials using combinations of AZD2014 and PTX for the treatment of solid tumors. Such combinations may also be employed for the design of novel targeted ATC treatment strategies.
PB  - Basel : Springer Nature
T2  - Cellular Oncology (Dordrecht)
T1  - Potential of the dual mTOR kinase inhibitor AZD2014 to overcome paclitaxel resistance in anaplastic thyroid carcinoma
VL  - 41
DO  - 10.1007/s13402-018-0380-x
SP  - 409
EP  - 426
ER  - 

@article{
author = "Milošević, Zorica and Banković, Jasna and Dinić, Jelena and Tsimplouli, Chrisiida and Sereti, Evangelia and Dragoj, Miodrag and Paunović, Verica and Milovanović, Zorka and Nešović, Marija and Tanić, Nikola and Dimas, Kostantinos and Pešić, Milica",
year = "2018",
abstract = "Purpose: Anaplastic thyroid carcinoma (ATC) is an aggressive, chemo-resistant malignancy. Chemo-resistance is often associated with changes in activity of the RAS/MAPK/ERK and PI3K/AKT/mTOR pathways and/or a high expression of ATP binding cassette (ABC) transporters, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). To assess the therapeutic efficacy in ATC of a combination of the dual mTOR kinase inhibitor vistusertib (AZD2014) and paclitaxel (PTX), we generated a new cell line (Rho-) via the selection of human thyroid carcinoma 8505C cells that exhibit a low accumulation of rhodamine 123, which serves as a P-gp and BCRP substrate.
Methods: Immunohistochemistry was used for P-gp and BCRP expression analyses in primary ATC patient samples. Spheroid formation and immunodeficient NSG mice were used for performing in vitro and in vivo tumorigenicity assays, respectively. MTT, flow-cytometry, fluorescent microscopy, cell death and proliferation assays, as well as migration, invasion and gelatin degradation assays, were used to assess the potential of AZD2014 to enhance the effects of PTX. ATC xenografts in SCID mice were used for evaluating in vivo treatment efficacies.
Results: Rho- cells were found to be 10-fold more resistant to PTX than 8505C cells and, in addition, to be more tumorigenic. We also found that AZD2014 sensitized Rho- cells to PTX by inhibiting proliferation and by inducing autophagy. The combined use of AZD2014 and PTX efficiently inhibited in vitro ATC cell migration and invasion. Subsequent in vivo xenograft studies indicated that the AZD2014 and PTX combination effectively suppressed ATC tumor growth.
Conclusions: Our data support results from recent phase I clinical trials using combinations of AZD2014 and PTX for the treatment of solid tumors. Such combinations may also be employed for the design of novel targeted ATC treatment strategies.",
publisher = "Basel : Springer Nature",
journal = "Cellular Oncology (Dordrecht)",
title = "Potential of the dual mTOR kinase inhibitor AZD2014 to overcome paclitaxel resistance in anaplastic thyroid carcinoma",
volume = "41",
doi = "10.1007/s13402-018-0380-x",
pages = "409-426"
}

Milošević, Z., Banković, J., Dinić, J., Tsimplouli, C., Sereti, E., Dragoj, M., Paunović, V., Milovanović, Z., Nešović, M., Tanić, N., Dimas, K.,& Pešić, M.. (2018). Potential of the dual mTOR kinase inhibitor AZD2014 to overcome paclitaxel resistance in anaplastic thyroid carcinoma. in Cellular Oncology (Dordrecht)
Basel : Springer Nature., 41, 409-426.
https://doi.org/10.1007/s13402-018-0380-x

Milošević Z, Banković J, Dinić J, Tsimplouli C, Sereti E, Dragoj M, Paunović V, Milovanović Z, Nešović M, Tanić N, Dimas K, Pešić M. Potential of the dual mTOR kinase inhibitor AZD2014 to overcome paclitaxel resistance in anaplastic thyroid carcinoma. in Cellular Oncology (Dordrecht). 2018;41:409-426.
doi:10.1007/s13402-018-0380-x .

Milošević, Zorica, Banković, Jasna, Dinić, Jelena, Tsimplouli, Chrisiida, Sereti, Evangelia, Dragoj, Miodrag, Paunović, Verica, Milovanović, Zorka, Nešović, Marija, Tanić, Nikola, Dimas, Kostantinos, Pešić, Milica, "Potential of the dual mTOR kinase inhibitor AZD2014 to overcome paclitaxel resistance in anaplastic thyroid carcinoma" in Cellular Oncology (Dordrecht), 41 (2018):409-426,
https://doi.org/10.1007/s13402-018-0380-x . .

TY  - JOUR
AU  - Jeremić, Marko
AU  - Dinić, Jelena
AU  - Pešić, Milica
AU  - Nešović, Marija
AU  - Novaković, Irena
AU  - Šegan, Dejan
AU  - Sladić, Dušan
PY  - 2018
UR  - http://www.doiserbia.nb.rs/Article.aspx?ID=0352-51391800062J
UR  - https://radar.ibiss.bg.ac.rs/123456789/3866
AB  - In this paper, the synthesis of fourteen alkylamino and arylamino derivatives of sesquiterpene quinone avarone and its model compound tert-butylquinone is described. Branched, cyclic, allylic and benzylic alkylamino/arylamino groups were introduced into the quinone moiety. For all the obtained derivatives, their biological activity and redox properties were studied. The cytotoxic activity of the synthesized derivatives towards multidrug resistant (MDR) human non-small cell lung carcinoma NCI-H460/R cells, their sensitive counterpart NCI-H460 and human normal keratinocytes (HaCaT) was investigated. The antimicrobial activity towards Gram-positive and Gram-negative bacteria, and fungal cultures was determined. Some of the synthesized derivatives showed selectivity for cancer cells, including MDR cells. Regarding their cell death induction potential, the most promising compounds were allylamino derivatives, preferentially triggering apoptosis, with high selectivity for cancer cells, including MDR cells. Several compounds showed promising antimicrobial activity, comparable to those of commercial antibiotic and antimycotic agents.
PB  - Serbian Chemical Society
T2  - Journal of the Serbian Chemical Society
T1  - Alkylamino and aralkylamino derivatives of avarone and its mimetic as selective agents against non-small cell lung cancer cells, their antibacterial and antifungal potential
IS  - 11
VL  - 83
DO  - 10.2298/JSC180627062J
SP  - 1193
EP  - 1207
ER  - 

@article{
author = "Jeremić, Marko and Dinić, Jelena and Pešić, Milica and Nešović, Marija and Novaković, Irena and Šegan, Dejan and Sladić, Dušan",
year = "2018",
abstract = "In this paper, the synthesis of fourteen alkylamino and arylamino derivatives of sesquiterpene quinone avarone and its model compound tert-butylquinone is described. Branched, cyclic, allylic and benzylic alkylamino/arylamino groups were introduced into the quinone moiety. For all the obtained derivatives, their biological activity and redox properties were studied. The cytotoxic activity of the synthesized derivatives towards multidrug resistant (MDR) human non-small cell lung carcinoma NCI-H460/R cells, their sensitive counterpart NCI-H460 and human normal keratinocytes (HaCaT) was investigated. The antimicrobial activity towards Gram-positive and Gram-negative bacteria, and fungal cultures was determined. Some of the synthesized derivatives showed selectivity for cancer cells, including MDR cells. Regarding their cell death induction potential, the most promising compounds were allylamino derivatives, preferentially triggering apoptosis, with high selectivity for cancer cells, including MDR cells. Several compounds showed promising antimicrobial activity, comparable to those of commercial antibiotic and antimycotic agents.",
publisher = "Serbian Chemical Society",
journal = "Journal of the Serbian Chemical Society",
title = "Alkylamino and aralkylamino derivatives of avarone and its mimetic as selective agents against non-small cell lung cancer cells, their antibacterial and antifungal potential",
number = "11",
volume = "83",
doi = "10.2298/JSC180627062J",
pages = "1193-1207"
}

Jeremić, M., Dinić, J., Pešić, M., Nešović, M., Novaković, I., Šegan, D.,& Sladić, D.. (2018). Alkylamino and aralkylamino derivatives of avarone and its mimetic as selective agents against non-small cell lung cancer cells, their antibacterial and antifungal potential. in Journal of the Serbian Chemical Society
Serbian Chemical Society., 83(11), 1193-1207.
https://doi.org/10.2298/JSC180627062J

Jeremić M, Dinić J, Pešić M, Nešović M, Novaković I, Šegan D, Sladić D. Alkylamino and aralkylamino derivatives of avarone and its mimetic as selective agents against non-small cell lung cancer cells, their antibacterial and antifungal potential. in Journal of the Serbian Chemical Society. 2018;83(11):1193-1207.
doi:10.2298/JSC180627062J .

Jeremić, Marko, Dinić, Jelena, Pešić, Milica, Nešović, Marija, Novaković, Irena, Šegan, Dejan, Sladić, Dušan, "Alkylamino and aralkylamino derivatives of avarone and its mimetic as selective agents against non-small cell lung cancer cells, their antibacterial and antifungal potential" in Journal of the Serbian Chemical Society, 83, no. 11 (2018):1193-1207,
https://doi.org/10.2298/JSC180627062J . .

TY  - JOUR
AU  - Milošević, Zorica
AU  - Banković, Jasna
AU  - Dinić, Jelena
AU  - Tsimplouli, Chrisiida
AU  - Sereti, Evangelia
AU  - Dragoj, Miodrag
AU  - Paunović, Verica
AU  - Milovanović, Zorka
AU  - Stepanović, Marija
AU  - Tanić, Nikola
AU  - Dimas, Kostantinos
AU  - Pešić, Milica
PY  - 2018
UR  - http://link.springer.com/10.1007/s13402-018-0380-x
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3128
AB  - PURPOSE Anaplastic thyroid carcinoma (ATC) is an aggressive, chemo-resistant malignancy. Chemo-resistance is often associated with changes in activity of the RAS/MAPK/ERK and PI3K/AKT/mTOR pathways and/or a high expression of ATP binding cassette (ABC) transporters, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). To assess the therapeutic efficacy in ATC of a combination of the dual mTOR kinase inhibitor vistusertib (AZD2014) and paclitaxel (PTX), we generated a new cell line (Rho-) via the selection of human thyroid carcinoma 8505C cells that exhibit a low accumulation of rhodamine 123, which serves as a P-gp and BCRP substrate. METHODS Immunohistochemistry was used for P-gp and BCRP expression analyses in primary ATC patient samples. Spheroid formation and immunodeficient NSG mice were used for performing in vitro and in vivo tumorigenicity assays, respectively. MTT, flow-cytometry, fluorescent microscopy, cell death and proliferation assays, as well as migration, invasion and gelatin degradation assays, were used to assess the potential of AZD2014 to enhance the effects of PTX. ATC xenografts in SCID mice were used for evaluating in vivo treatment efficacies. RESULTS Rho- cells were found to be 10-fold more resistant to PTX than 8505C cells and, in addition, to be more tumorigenic. We also found that AZD2014 sensitized Rho- cells to PTX by inhibiting proliferation and by inducing autophagy. The combined use of AZD2014 and PTX efficiently inhibited in vitro ATC cell migration and invasion. Subsequent in vivo xenograft studies indicated that the AZD2014 and PTX combination effectively suppressed ATC tumor growth. CONCLUSIONS Our data support results from recent phase I clinical trials using combinations of AZD2014 and PTX for the treatment of solid tumors. Such combinations may also be employed for the design of novel targeted ATC treatment strategies.
T2  - Cellular Oncology (Dordrecht)
T1  - Potential of the dual mTOR kinase inhibitor AZD2014 to overcome paclitaxel resistance in anaplastic thyroid carcinoma.
IS  - 4
VL  - 41
DO  - 10.1007/s13402-018-0380-x
SP  - 409
EP  - 426
ER  - 

@article{
author = "Milošević, Zorica and Banković, Jasna and Dinić, Jelena and Tsimplouli, Chrisiida and Sereti, Evangelia and Dragoj, Miodrag and Paunović, Verica and Milovanović, Zorka and Stepanović, Marija and Tanić, Nikola and Dimas, Kostantinos and Pešić, Milica",
year = "2018",
abstract = "PURPOSE Anaplastic thyroid carcinoma (ATC) is an aggressive, chemo-resistant malignancy. Chemo-resistance is often associated with changes in activity of the RAS/MAPK/ERK and PI3K/AKT/mTOR pathways and/or a high expression of ATP binding cassette (ABC) transporters, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). To assess the therapeutic efficacy in ATC of a combination of the dual mTOR kinase inhibitor vistusertib (AZD2014) and paclitaxel (PTX), we generated a new cell line (Rho-) via the selection of human thyroid carcinoma 8505C cells that exhibit a low accumulation of rhodamine 123, which serves as a P-gp and BCRP substrate. METHODS Immunohistochemistry was used for P-gp and BCRP expression analyses in primary ATC patient samples. Spheroid formation and immunodeficient NSG mice were used for performing in vitro and in vivo tumorigenicity assays, respectively. MTT, flow-cytometry, fluorescent microscopy, cell death and proliferation assays, as well as migration, invasion and gelatin degradation assays, were used to assess the potential of AZD2014 to enhance the effects of PTX. ATC xenografts in SCID mice were used for evaluating in vivo treatment efficacies. RESULTS Rho- cells were found to be 10-fold more resistant to PTX than 8505C cells and, in addition, to be more tumorigenic. We also found that AZD2014 sensitized Rho- cells to PTX by inhibiting proliferation and by inducing autophagy. The combined use of AZD2014 and PTX efficiently inhibited in vitro ATC cell migration and invasion. Subsequent in vivo xenograft studies indicated that the AZD2014 and PTX combination effectively suppressed ATC tumor growth. CONCLUSIONS Our data support results from recent phase I clinical trials using combinations of AZD2014 and PTX for the treatment of solid tumors. Such combinations may also be employed for the design of novel targeted ATC treatment strategies.",
journal = "Cellular Oncology (Dordrecht)",
title = "Potential of the dual mTOR kinase inhibitor AZD2014 to overcome paclitaxel resistance in anaplastic thyroid carcinoma.",
number = "4",
volume = "41",
doi = "10.1007/s13402-018-0380-x",
pages = "409-426"
}

Milošević, Z., Banković, J., Dinić, J., Tsimplouli, C., Sereti, E., Dragoj, M., Paunović, V., Milovanović, Z., Stepanović, M., Tanić, N., Dimas, K.,& Pešić, M.. (2018). Potential of the dual mTOR kinase inhibitor AZD2014 to overcome paclitaxel resistance in anaplastic thyroid carcinoma.. in Cellular Oncology (Dordrecht), 41(4), 409-426.
https://doi.org/10.1007/s13402-018-0380-x

Milošević Z, Banković J, Dinić J, Tsimplouli C, Sereti E, Dragoj M, Paunović V, Milovanović Z, Stepanović M, Tanić N, Dimas K, Pešić M. Potential of the dual mTOR kinase inhibitor AZD2014 to overcome paclitaxel resistance in anaplastic thyroid carcinoma.. in Cellular Oncology (Dordrecht). 2018;41(4):409-426.
doi:10.1007/s13402-018-0380-x .

Milošević, Zorica, Banković, Jasna, Dinić, Jelena, Tsimplouli, Chrisiida, Sereti, Evangelia, Dragoj, Miodrag, Paunović, Verica, Milovanović, Zorka, Stepanović, Marija, Tanić, Nikola, Dimas, Kostantinos, Pešić, Milica, "Potential of the dual mTOR kinase inhibitor AZD2014 to overcome paclitaxel resistance in anaplastic thyroid carcinoma." in Cellular Oncology (Dordrecht), 41, no. 4 (2018):409-426,
https://doi.org/10.1007/s13402-018-0380-x . .