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Drug resistance mainly drives GBM patients to poor prognoses because drug\u2010resistant glioblastoma cells highly defend against apoptotic insults. This study was designed to evaluate the effects of cobalt chloride (CoCl<jats:sub>2<\/jats:sub>) on hypoxic stress, autophagy, and resulting apoptosis of human and mouse drug\u2010resistant glioblastoma cells. Treatment of drug\u2010resistant glioblastoma cells with CoCl<jats:sub>2<\/jats:sub> increased levels of hypoxia\u2010inducible factor\u2010 (HIF\u2010) 1<jats:italic>\u03b1<\/jats:italic> and triggered hypoxic stress. In parallel, the CoCl<jats:sub>2<\/jats:sub>\u2010induced hypoxia decreased mitochondrial ATP synthesis, cell proliferation, and survival in chemoresistant glioblastoma cells. Interestingly, CoCl<jats:sub>2<\/jats:sub> elevated the ratio of light chain (LC)3\u2010II over LC3\u2010I in TMZ\u2010resistant glioblastoma cells and subsequently induced cell autophagy. Analyses by loss\u2010 and gain\u2010of\u2010function strategies further confirmed the effects of the CoCl<jats:sub>2<\/jats:sub>\u2010induced hypoxia on autophagy of drug\u2010resistant glioblastoma cells. Furthermore, knocking down HIF\u20101<jats:italic>\u03b1<\/jats:italic> concurrently lessened CoCl<jats:sub>2<\/jats:sub>\u2010induced cell autophagy. As to the mechanisms, the CoCl<jats:sub>2<\/jats:sub>\u2010induced hypoxia decreased levels of phosphoinositide 3\u2010kinase (PI3K) and successive phosphorylations of AKT and mammalian target of rapamycin (mTOR) in TMZ\u2010resistant glioblastoma cells. Interestingly, long\u2010term exposure of human chemoresistant glioblastoma cells to CoCl<jats:sub>2<\/jats:sub> sequentially triggered activation of caspases\u20103 and \u20106, DNA fragmentation, and cell apoptosis. However, pretreatment with 3\u2010methyladenine, an inhibitor of autophagy, significantly attenuated the CoCl<jats:sub>2<\/jats:sub>\u2010induced autophagy and subsequent apoptotic insults. Taken together, this study showed that long\u2010term treatment with CoCl<jats:sub>2<\/jats:sub> can induce hypoxia and subsequent autophagic apoptosis of drug\u2010resistant glioblastoma cells via targeting the PI3K\u2010AKT\u2010mTOR pathway. Thus, combined with traditional prescriptions, CoCl<jats:sub>2<\/jats:sub>\u2010induced autophagic apoptosis can be clinically applied as a <jats:italic>de novo<\/jats:italic> strategy for therapy of drug\u2010resistant GBM patients.<\/jats:p>","DOI":"10.1155\/2021\/5558618","type":"journal-article","created":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T18:32:52Z","timestamp":1622226772000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Hypoxia Induced by Cobalt Chloride Triggers Autophagic Apoptosis of Human and Mouse Drug\u2010Resistant Glioblastoma Cells through Targeting the PI3K\u2010AKT\u2010mTOR Signaling 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