الفهرس | Only 14 pages are availabe for public view |
Abstract Abstract !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!” ” ” -1- !!Sunitinib malate, a multityrosine kinase inhibitor, is currently used in the treatment of imatinib-resistant gastrointestinal stromal tumor, renal cell carcinoma and pancreatic neuroendocrine tumors. Although there are ongoing clinical trials assessing its efficacy in other types of cancer, increasing studies report emergence of sunitinib resistance. In the current study, we aimed to explore the interplay between sunitinib cytotoxicity and autophagy. Autophagy has dual roles in cancer; tumor cells utilize it to survive under nutrient deprivation. Conversely, several anti-cancer agents have been shown to trigger excessive autophagy that may contribute to their cytotoxicity. Surprisingly, we found that sunitinib exhibited “concentration-range” dependent effect on autophagy. Clinically-relevant concentrations of sunitinib inhibited autophagy whereas higher ones switched on the autophagic machinery. The present study also showed that autophagic cell death is required for mediating sunitinib cytotoxicity. We then explored whether sunitinib can modulate mTOR pathway and Bcl-2 family of proteins; both are crucial autophagy regulators that play prosurvival roles in cancer. Strikingly, lower concentrations of sunitinib increased Mcl-1 level and activated mTOR pathway. In contrast, higher concentrations decreased Mcl-1 level. Ablation of Mcl-1 by RNAi sensitized cancer cells to sunitinib. Outer–membrane but not matrix |