TY  - JOUR
AU  - Stepanović, Ana
AU  - Terzić Jovanović, Nataša
AU  - Korać, Aleksandra
AU  - Zlatović, Mario
AU  - Nikolić, Igor
AU  - Opsenica, Igor
AU  - Pešić, Milica
PY  - 2024
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6664
AB  - Two novel hybrid compounds, CON1 and CON2, have been developed by combining sclareol (SC) and doxorubicin (DOX) into a single molecular entity. These hybrid compounds have a 1:1 molar ratio of covalently linked SC and DOX. They have demonstrated promising anticancer properties, especially in glioblastoma cells, and have also shown potential in treating multidrug-resistant (MDR) cancer cells that express the P-glycoprotein (P-gp) membrane transporter. CON1 and CON2 form nanoparticles, as confirmed by Zetasizer, transmission electron microscopy (TEM), and chemical modeling. TEM also showed that CON1 and CON2 can be found in glioblastoma cells, specifically in the cytoplasm, different organelles, nucleus, and nucleolus. To examine the anticancer properties, the U87 glioblastoma cell line, and its corresponding multidrug-resistant U87-TxR cell line, as well as patient-derived astrocytoma grade 3 cells (ASC), were used, while normal human lung fibroblasts were used to determine the selectivity. CON1 and CON2 exhibited better resistance and selectivity profiles than DOX, showing less cytotoxicity, as evidenced by real-time cell analysis, DNA damage determination, cell death induction, mitochondrial respiration, and mitochondrial membrane depolarization studies. Cell cycle analysis and the β-galactosidase activity assay suggested that glioblastoma cells die by senescence following CON1 treatment. Overall, CON1 and CON2 showed great potential as they have better anticancer features than DOX. They are promising candidates for additional preclinical and clinical studies on glioblastoma.
PB  - Elsevier Masson SAS
T2  - Biomedicine & Pharmacotherapy
T1  - Novel hybrid compounds of sclareol and doxorubicin as potential anticancer nanotherapy for glioblastoma
VL  - 174
DO  - 10.1016/j.biopha.2024.116496
SP  - 116496
ER  - 

@article{
author = "Stepanović, Ana and Terzić Jovanović, Nataša and Korać, Aleksandra and Zlatović, Mario and Nikolić, Igor and Opsenica, Igor and Pešić, Milica",
year = "2024",
abstract = "Two novel hybrid compounds, CON1 and CON2, have been developed by combining sclareol (SC) and doxorubicin (DOX) into a single molecular entity. These hybrid compounds have a 1:1 molar ratio of covalently linked SC and DOX. They have demonstrated promising anticancer properties, especially in glioblastoma cells, and have also shown potential in treating multidrug-resistant (MDR) cancer cells that express the P-glycoprotein (P-gp) membrane transporter. CON1 and CON2 form nanoparticles, as confirmed by Zetasizer, transmission electron microscopy (TEM), and chemical modeling. TEM also showed that CON1 and CON2 can be found in glioblastoma cells, specifically in the cytoplasm, different organelles, nucleus, and nucleolus. To examine the anticancer properties, the U87 glioblastoma cell line, and its corresponding multidrug-resistant U87-TxR cell line, as well as patient-derived astrocytoma grade 3 cells (ASC), were used, while normal human lung fibroblasts were used to determine the selectivity. CON1 and CON2 exhibited better resistance and selectivity profiles than DOX, showing less cytotoxicity, as evidenced by real-time cell analysis, DNA damage determination, cell death induction, mitochondrial respiration, and mitochondrial membrane depolarization studies. Cell cycle analysis and the β-galactosidase activity assay suggested that glioblastoma cells die by senescence following CON1 treatment. Overall, CON1 and CON2 showed great potential as they have better anticancer features than DOX. They are promising candidates for additional preclinical and clinical studies on glioblastoma.",
publisher = "Elsevier Masson SAS",
journal = "Biomedicine & Pharmacotherapy",
title = "Novel hybrid compounds of sclareol and doxorubicin as potential anticancer nanotherapy for glioblastoma",
volume = "174",
doi = "10.1016/j.biopha.2024.116496",
pages = "116496"
}

Stepanović, A., Terzić Jovanović, N., Korać, A., Zlatović, M., Nikolić, I., Opsenica, I.,& Pešić, M.. (2024). Novel hybrid compounds of sclareol and doxorubicin as potential anticancer nanotherapy for glioblastoma. in Biomedicine & Pharmacotherapy
Elsevier Masson SAS., 174, 116496.
https://doi.org/10.1016/j.biopha.2024.116496

Stepanović A, Terzić Jovanović N, Korać A, Zlatović M, Nikolić I, Opsenica I, Pešić M. Novel hybrid compounds of sclareol and doxorubicin as potential anticancer nanotherapy for glioblastoma. in Biomedicine & Pharmacotherapy. 2024;174:116496.
doi:10.1016/j.biopha.2024.116496 .

Stepanović, Ana, Terzić Jovanović, Nataša, Korać, Aleksandra, Zlatović, Mario, Nikolić, Igor, Opsenica, Igor, Pešić, Milica, "Novel hybrid compounds of sclareol and doxorubicin as potential anticancer nanotherapy for glioblastoma" in Biomedicine & Pharmacotherapy, 174 (2024):116496,
https://doi.org/10.1016/j.biopha.2024.116496 . .

TY  - CONF
AU  - Lupšić, Ema
AU  - Dinić, Jelena
AU  - Nikolić, Igor
AU  - Jovanović Stojanov, Sofija
AU  - Pešić, Milica
AU  - Podolski-Renić, Ana
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6381
AB  - Background:  High-grade gliomas are the most frequently diagnosed malignant brain tumors in adults, with a very unfavorable prognosis. Although various strategies have been applied in the clinical setting, no significant progress has been made in the treatment of high-grade glioma. Clinical trials continue to expand into new approaches such as targeted agents and immunotherapy. Here, we performed pharmacological screening of tyrosine kinase inhibitors (TKIs) on patient-derived glioma cells ex vivo and assessed the expression of multidrug resistance (MDR) marker in glioma and stromal (non-glioma) cells. The effects of TKIs have been compared with chemotherapeutic agents approved for the treatment of high-grade glioma. Material and Methods: Primary patient-derived cell cultures were established from resections of high-grade gliomas. After short-term culturing (2-3 weeks), a mixed population of glioma and non-glioma cells was treated with 4 TKIs (alectinib, dabrafenib, trametinib, and nintedanib), as well as temozolomide (TMZ) and carmustine (BCNU). The maximum achieved concentration in human plasma during therapy (Cmax) was set as the upper limit and 4 lower concentrations were also used during the study. An immunofluorescence assay allowing discrimination of glial fibrillary acidic protein antibody-positive glioma cells versus negative non-glioma cells was performed using an ImageXpress Pico high-content imager (Molecular Devices) with CellReporterXpress 2.9 software. The MDR marker (ABCB1) was analyzed with the corresponding antibody in the same immunoassay. Results: Among the compounds tested, alectinib and TMZ did not affect cell growth and did not change the number of ABCB1-positive cells. Other compounds significantly inhibited the growth of glioma cells. However, they were not selective towards glioma cells, on the contrary, they showed greater cytotoxicity in non-glioma cells. The number of glioma cells positive for the ABCB1 marker increased significantly after treatment with dabrafenib, nintedanib, and BCNU, while trametinib and did not change ABCB1 expression in glioma cells. Stromal (non-glioma) cells generally followed the pattern of ABCB1 observed in glioma cells. Conclusions: Novel functional immunoassay may provide valuable information on the sensitivity of high-grade gliomas to different TKIs and possible treatment outcomes based on the expression of MDR marker.
PB  - Belgrade, Serbia: Serbian Associaton for Cancer Research
C3  - Proceedings book of The Sixth Congress of The Serbian Association for Cancer Research with international participation: From Collaboration to Innovation in Cancer Research; 2023 Oct 2-4; Belgrade, Serbia
T1  - The effect of tyrosine kinase inhibitors in high-grade glioma patient-derived cells
SP  - 84
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_6381
ER  - 

@conference{
author = "Lupšić, Ema and Dinić, Jelena and Nikolić, Igor and Jovanović Stojanov, Sofija and Pešić, Milica and Podolski-Renić, Ana",
year = "2023",
abstract = "Background:  High-grade gliomas are the most frequently diagnosed malignant brain tumors in adults, with a very unfavorable prognosis. Although various strategies have been applied in the clinical setting, no significant progress has been made in the treatment of high-grade glioma. Clinical trials continue to expand into new approaches such as targeted agents and immunotherapy. Here, we performed pharmacological screening of tyrosine kinase inhibitors (TKIs) on patient-derived glioma cells ex vivo and assessed the expression of multidrug resistance (MDR) marker in glioma and stromal (non-glioma) cells. The effects of TKIs have been compared with chemotherapeutic agents approved for the treatment of high-grade glioma. Material and Methods: Primary patient-derived cell cultures were established from resections of high-grade gliomas. After short-term culturing (2-3 weeks), a mixed population of glioma and non-glioma cells was treated with 4 TKIs (alectinib, dabrafenib, trametinib, and nintedanib), as well as temozolomide (TMZ) and carmustine (BCNU). The maximum achieved concentration in human plasma during therapy (Cmax) was set as the upper limit and 4 lower concentrations were also used during the study. An immunofluorescence assay allowing discrimination of glial fibrillary acidic protein antibody-positive glioma cells versus negative non-glioma cells was performed using an ImageXpress Pico high-content imager (Molecular Devices) with CellReporterXpress 2.9 software. The MDR marker (ABCB1) was analyzed with the corresponding antibody in the same immunoassay. Results: Among the compounds tested, alectinib and TMZ did not affect cell growth and did not change the number of ABCB1-positive cells. Other compounds significantly inhibited the growth of glioma cells. However, they were not selective towards glioma cells, on the contrary, they showed greater cytotoxicity in non-glioma cells. The number of glioma cells positive for the ABCB1 marker increased significantly after treatment with dabrafenib, nintedanib, and BCNU, while trametinib and did not change ABCB1 expression in glioma cells. Stromal (non-glioma) cells generally followed the pattern of ABCB1 observed in glioma cells. Conclusions: Novel functional immunoassay may provide valuable information on the sensitivity of high-grade gliomas to different TKIs and possible treatment outcomes based on the expression of MDR marker.",
publisher = "Belgrade, Serbia: Serbian Associaton for Cancer Research",
journal = "Proceedings book of The Sixth Congress of The Serbian Association for Cancer Research with international participation: From Collaboration to Innovation in Cancer Research; 2023 Oct 2-4; Belgrade, Serbia",
title = "The effect of tyrosine kinase inhibitors in high-grade glioma patient-derived cells",
pages = "84",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_6381"
}

Lupšić, E., Dinić, J., Nikolić, I., Jovanović Stojanov, S., Pešić, M.,& Podolski-Renić, A.. (2023). The effect of tyrosine kinase inhibitors in high-grade glioma patient-derived cells. in Proceedings book of The Sixth Congress of The Serbian Association for Cancer Research with international participation: From Collaboration to Innovation in Cancer Research; 2023 Oct 2-4; Belgrade, Serbia
Belgrade, Serbia: Serbian Associaton for Cancer Research., 84.
https://hdl.handle.net/21.15107/rcub_ibiss_6381

Lupšić E, Dinić J, Nikolić I, Jovanović Stojanov S, Pešić M, Podolski-Renić A. The effect of tyrosine kinase inhibitors in high-grade glioma patient-derived cells. in Proceedings book of The Sixth Congress of The Serbian Association for Cancer Research with international participation: From Collaboration to Innovation in Cancer Research; 2023 Oct 2-4; Belgrade, Serbia. 2023;:84.
https://hdl.handle.net/21.15107/rcub_ibiss_6381 .

Lupšić, Ema, Dinić, Jelena, Nikolić, Igor, Jovanović Stojanov, Sofija, Pešić, Milica, Podolski-Renić, Ana, "The effect of tyrosine kinase inhibitors in high-grade glioma patient-derived cells" in Proceedings book of The Sixth Congress of The Serbian Association for Cancer Research with international participation: From Collaboration to Innovation in Cancer Research; 2023 Oct 2-4; Belgrade, Serbia (2023):84,
https://hdl.handle.net/21.15107/rcub_ibiss_6381 .

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  - 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  - 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 .