Journal
LIFE-BASEL
Volume 12, Issue 10, Pages -Publisher
MDPI
DOI: 10.3390/life12101503
Keywords
glioblastoma; autophagy; Src tyrosine kinase inhibitor; multidrug resistance
Categories
Funding
- Ministry of Education, Science and Technological Development of the Republic of Serbia [451-03-68/2022-14/200007, 451-03-68/2022-14/200042]
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Drug resistance is a major challenge in treating glioblastoma. Autophagy plays a crucial role in drug resistance, and the use of autophagy inhibitors can enhance the effectiveness of targeted therapy. This study shows that two Src tyrosine kinase inhibitors can induce autophagy in glioblastoma cells, and inhibiting autophagy can increase the anticancer effects of these inhibitors.
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.
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