Autophagy Inhibition Enhances Anti-Glioblastoma Effects of Pyrazolo[3,4-d]pyrimidine Tyrosine Kinase Inhibitors
2022
Authors:
Jovanović Stojanov, SofijaStepanović, Ana
Ljujić, Mila
Lupšić, Ema
Schenone, Silvia
Pešić, Milica
Dinić, Jelena
Document Type:
Article (Published version)
Metadata
Show full item recordAbstract:
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.
Keywords:
glioblastoma; autophagy; Src tyrosine kinase inhibitor; multidrug resistanceSource:
Life, 2022, 12, 10, 1503-Funding / projects:
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200007 (University of Belgrade, Institute for Biological Research 'Siniša Stanković') (RS-MESTD-inst-2020-200007)
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200042 (University of Belgrade, Institute of Molecular Genetics and Genetic Engineering) (RS-MESTD-inst-2020-200042)
DOI: 10.3390/life12101503
ISSN: 2075-1729
PubMed: 36294938