Autophagy inhibition synergizes with calcium mobilization to achieve efficient therapy of malignant gliomas.
作者： Ha Thi Vu , Masahiko Kobayashi , Ahmed M. Hegazy , Yuko Tadokoro , Masaya Ueno
DOI: 10.1111/CAS.13695
关键词: Temozolomide 、 Glioma 、 Nigericin 、 ATG5 、 Reactive oxygen species 、 PI3K/AKT/mTOR pathway 、 Chemistry 、 Cancer cell 、 Autophagy 、 Cancer research
摘要: Autophagy plays a critical role in tumorigenesis, but how autophagy contributes to cancer cells' responses chemotherapeutics remains controversial. To investigate the roles of malignant gliomas, we used CRISPR/CAS9 knock out ATG5 gene, which is essential for autophagosome formation, tumor cells derived from patients with glioblastoma. While disruption inhibited autophagy, it did not change phenotypes glioma and alter their sensitivity temozolomide, an agent glioblastoma patient therapy. Screening anticancer drug library identified compounds that showed greater efficacy ATG5-knockout compared control. several selected compounds, including nigericin salinomycin, remarkably induced potent inducers by mTOR inhibition exhibit ATG5-dependent cytoprotective effects. Nigericin combination deficiency synergistically suppressed spheroid formation manner mitigated Ca2+ chelation or CaMKK inhibition, indicating that, calcium-mobilizing contribute efficient therapeutics. treated increased mitochondria-derived reactive oxygen species apoptosis controls, protects mitochondrial species-mediated damage. Finally, using patient-derived xenograft model, demonstrated chloroquine, pharmacological inhibitor, dramatically enhanced this study. Our findings propose novel therapeutic strategy are combined inhibitors treat
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