Modulation of Sunitinib Cytotoxicity: Emphasis on Cell Death

Abstract

Cancer is among the frequent causes of human death in the world. It has been proven that overexpression, mutations and constitutive activation of several tyrosine kinase receptors contribute to tumorigenesis. Sunitinib, a small molecule tyrosine kinase inhibitor, has been approved by the FDA to be used in the treatment of renal cell carcinoma, imatinib-resistant GIST and pancreatic neuroendocrine tumor primarily through its inhibitory actions on various tyrosine kinase receptors as VEGFR, c-kit and PDGFR. Over the last few years, increasing studies reported rapid development of sunitinib-resistant cells. It has been shown that pro-survival mechanisms have been activated in sunitinib-resistant cancer cells. Autophagy is a double-edged weapon; on one side, it is regarded as programmed cell death type II through which several chemotherapeutic agents mediate its cytotoxicity. On the other side, cancer cells may induce autophagy as a cytoprotective mechanism. In this regards, relevant studies reported conflicting data regarding the stimulatory versus inhibitory effect of sunitinib on autophagy. To our knowledge, the current study is the first to explain the differential modulatory effect of sunitinib on human colorectal cancer (HCT116), cervical cancer (Hela), osteosarcoma (U2OS) Summary and conclusions _____________________________________________________________