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TMZ treatment causes DNA damage that results in tumor cell apoptosis and increases the survival rate of GBM patients. However, chemoresistance as a result of TMZ\u2010induced autophagy significantly reduces this anticancer effects over time. Statins are competitive inhibitors of HMG\u2010CoA reductase, the rate\u2010limiting enzyme of the mevalonate (MEV) cascade. Statins are best known for their cholesterol (CH)\u2010lowering effect. Long\u2010term consumption of statins, prior to and in parallel with other cancer therapeutic approaches, has been reported to increase the survival rate of patients with various forms of cancers. In this study, we investigated the potentiation of TMZ\u2010induced apoptosis by simvastatin (Simva) in human GBM cell lines and patient GBM cells, using cell monolayers and three\u2010dimensional cell culture systems. The incubation of cells with a combination of Simva and TMZ resulted in a significant increase in apoptotic cells compared to cells treated with TMZ alone. Incubation of cells with CH or MEV cascade intermediates failed to compensate the decrease in cell viability induced by the combined Simva and TMZ treatment. Simva treatment inhibited the autophagy flux induced by TMZ by blocking autophago\u2010lysosome formation. Our results suggest that Simva sensitizes GBM cells to TMZ\u2010induced cell death in a MEV cascade\u2010independent manner and identifies the inhibition of autophagosome\u2010lysosome fusion as a promising therapeutic strategy in the treatment of GBM.<\/jats:p>","DOI":"10.1111\/febs.15069","type":"journal-article","created":{"date-parts":[[2019,9,23]],"date-time":"2019-09-23T14:35:18Z","timestamp":1569249318000},"page":"1005-1034","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":109,"title":["Simvastatin increases temozolomide\u2010induced cell death by targeting the fusion of autophagosomes and lysosomes"],"prefix":"10.1111","volume":"287","author":[{"given":"Shahla","family":"Shojaei","sequence":"first","affiliation":[{"name":"Department of Human Anatomy and Cell Science Max Rady College of Medicine Rady Faculty of Health Sciences University of Manitoba Winnipeg Canada"},{"name":"Laboratory for Innovation in Microengineering 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