Autophagy Inhibition Enhances Anti-Glioblastoma Effects of Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors
Аутори
Jovanović Stojanov, SofijaKostić, Ana
Ljujić, Mila
Lupšić, Ema
Schenone, Silvia
Pešić, Milica
Dinić, Jelena
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
Drug resistance presents a major obstacle to the successful treatment of glioblastoma. Autophagy plays a key role in drug resistance, particularly in relation to targeted therapy, which has prompted the use of autophagy inhibitors to increase the effectiveness of targeted therapeutics. The ability of two Src tyrosine kinase inhibitors, Si306 and its prodrug pro-Si306, to induce autophagy was evaluated in the human glioblastoma cell line U87 and its multidrug-resistant counterpart U87-TxR. Autophagy markers were assessed by flow cytometry, microscopy, and Western blot, and induction of autophagy by these compounds was demonstrated after 3 h as well as 48 h. The effects of Si306 and pro-Si306 on cell proliferation and cell death were examined in the presence or absence of autophagy inhibition by bafilomycin A1. Combined treatments of Si306 and pro-Si306 with bafilomycin A1 were synergistic in nature, and the inhibition of autophagy sensitized glioblastoma cells to Src tyrosine kinase inh...ibitors. Si306 and pro-Si306 more strongly inhibited cell proliferation and triggered necrosis in combination with bafilomycin A1. Our findings suggest that modulation of Si306- and pro-Si306-induced autophagy can be used to enhance the anticancer effects of these Src tyrosine kinase inhibitors and overcome the drug-resistant phenotype in glioblastoma cells.
Кључне речи:
autophagy / glioblastoma / multidrug resistance / Src tyrosine kinase inhibitorИзвор:
Life, 2022, 12, 10, 1503-Финансирање / пројекти:
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200007 (Универзитет у Београду, Институт за биолошка истраживања 'Синиша Станковић') (RS-MESTD-inst-2020-200007)
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200042 (Универзитет у Београду, Институт за молекуларну генетику и генетичко инжењерство) (RS-MESTD-inst-2020-200042)
Институција/група
Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Jovanović Stojanov, Sofija AU - Kostić, Ana AU - Ljujić, Mila AU - Lupšić, Ema AU - Schenone, Silvia AU - Pešić, Milica AU - Dinić, Jelena PY - 2022 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/1656 AB - Drug resistance presents a major obstacle to the successful treatment of glioblastoma. Autophagy plays a key role in drug resistance, particularly in relation to targeted therapy, which has prompted the use of autophagy inhibitors to increase the effectiveness of targeted therapeutics. The ability of two Src tyrosine kinase inhibitors, Si306 and its prodrug pro-Si306, to induce autophagy was evaluated in the human glioblastoma cell line U87 and its multidrug-resistant counterpart U87-TxR. Autophagy markers were assessed by flow cytometry, microscopy, and Western blot, and induction of autophagy by these compounds was demonstrated after 3 h as well as 48 h. The effects of Si306 and pro-Si306 on cell proliferation and cell death were examined in the presence or absence of autophagy inhibition by bafilomycin A1. Combined treatments of Si306 and pro-Si306 with bafilomycin A1 were synergistic in nature, and the inhibition of autophagy sensitized glioblastoma cells to Src tyrosine kinase inhibitors. Si306 and pro-Si306 more strongly inhibited cell proliferation and triggered necrosis in combination with bafilomycin A1. Our findings suggest that modulation of Si306- and pro-Si306-induced autophagy can be used to enhance the anticancer effects of these Src tyrosine kinase inhibitors and overcome the drug-resistant phenotype in glioblastoma cells. T2 - Life T2 - Life T1 - Autophagy Inhibition Enhances Anti-Glioblastoma Effects of Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors IS - 10 SP - 1503 VL - 12 DO - 10.3390/life12101503 ER -
@article{ author = "Jovanović Stojanov, Sofija and Kostić, Ana and Ljujić, Mila and Lupšić, Ema and Schenone, Silvia and Pešić, Milica and Dinić, Jelena", year = "2022", abstract = "Drug resistance presents a major obstacle to the successful treatment of glioblastoma. Autophagy plays a key role in drug resistance, particularly in relation to targeted therapy, which has prompted the use of autophagy inhibitors to increase the effectiveness of targeted therapeutics. The ability of two Src tyrosine kinase inhibitors, Si306 and its prodrug pro-Si306, to induce autophagy was evaluated in the human glioblastoma cell line U87 and its multidrug-resistant counterpart U87-TxR. Autophagy markers were assessed by flow cytometry, microscopy, and Western blot, and induction of autophagy by these compounds was demonstrated after 3 h as well as 48 h. The effects of Si306 and pro-Si306 on cell proliferation and cell death were examined in the presence or absence of autophagy inhibition by bafilomycin A1. Combined treatments of Si306 and pro-Si306 with bafilomycin A1 were synergistic in nature, and the inhibition of autophagy sensitized glioblastoma cells to Src tyrosine kinase inhibitors. Si306 and pro-Si306 more strongly inhibited cell proliferation and triggered necrosis in combination with bafilomycin A1. Our findings suggest that modulation of Si306- and pro-Si306-induced autophagy can be used to enhance the anticancer effects of these Src tyrosine kinase inhibitors and overcome the drug-resistant phenotype in glioblastoma cells.", journal = "Life, Life", title = "Autophagy Inhibition Enhances Anti-Glioblastoma Effects of Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors", number = "10", pages = "1503", volume = "12", doi = "10.3390/life12101503" }
Jovanović Stojanov, S., Kostić, A., Ljujić, M., Lupšić, E., Schenone, S., Pešić, M.,& Dinić, J.. (2022). Autophagy Inhibition Enhances Anti-Glioblastoma Effects of Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors. in Life, 12(10), 1503. https://doi.org/10.3390/life12101503
Jovanović Stojanov S, Kostić A, Ljujić M, Lupšić E, Schenone S, Pešić M, Dinić J. Autophagy Inhibition Enhances Anti-Glioblastoma Effects of Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors. in Life. 2022;12(10):1503. doi:10.3390/life12101503 .
Jovanović Stojanov, Sofija, Kostić, Ana, Ljujić, Mila, Lupšić, Ema, Schenone, Silvia, Pešić, Milica, Dinić, Jelena, "Autophagy Inhibition Enhances Anti-Glioblastoma Effects of Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors" in Life, 12, no. 10 (2022):1503, https://doi.org/10.3390/life12101503 . .