Sensitization of Glioma Cells by X-Linked Inhibitor of Apoptosis Protein Knockdown

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Objective: Glioblastomas are a kind of cancer with high resistance to treatments, requiring more efficient alternatives of treatment. X-linked inhibitor of apoptosis (XIAP) is highly expressed in gliomas and, due to its inhibition of caspases, can participate in resistance to therapy. Here we test the sensitization of glioma cells with XIAP gene knockdown (KD) to drugs used in chemotherapy. Methods: We silenced XIAP expression in U87MG glioblastoma using stable shRNA, and cells were treated with taxol, BCNU, temozolomide, cisplatin, etoposide, resveratrol (Rsv), vincristine and doxorubicin. We analyzed cell viability, cell cycle, apoptosis and senescence. Results: XIAP KD cells were more sensitive to etoposide, Rsv, vincristine and doxorubicin compared to wild-type (WT) cells. Doxorubicin 1 µM and vincristine 100 nM induced higher activation of caspases after 24 h and doxorubicin induced a higher degree of senescence induction in XIAP KD cells in relation to WT cells. Phospho-p53 and phospho-H2Ax Western blot indicate subsequent DNA damage as an important effector of doxorubicin-induced death. Conclusions: This study suggests that XIAP inhibitors may sensitize gliomas to certain drugs and induce death and that the mechanisms of sensitization involve apoptosis, senescence and p53 signaling.