targeting the anti-apoptotic protein c-flip for cancer therapy针对抗凋亡蛋白c-flip癌症治疗.pdf

Cancers 2011, 3, 1639-1671; doi:10.3390/cancers3021639 OPEN ACCESS cancers ISSN 2072-6694 /journal/cancers Review Targeting the Anti-Apoptotic Protein c-FLIP for Cancer Therapy Ahmad R. Safa 1,2,* and Karen E. Pollok 1,2,3 1 Department of Pharmacology and Toxicology, Indiana University School of Medicine, 980 W. Walnut Street, R3-C524, Indianapolis, IN 46202, USA 2 Indiana University Simon Cancer Center, Indiana University School of Medicine, 980 W. Walnut Street, R3-C524, Indianapolis, IN 46202, USA 3 Herman B. Wells Center for Pediatric Research, 980 W. Walnut Street, R3-C524, Indianapolis, IN 46202, USA; E-Mail: kpollok@ (K.E.P) * Author to whom correspondence should be addressed; E-Mail: asafa@; Tel.: +1-317-278-4952; Fax: +1-317-274-8046. Received: 26 February 2011; in revised form: 15 March 2011 / Accepted: 16 March 2011 / Published: 29 March 2011 Abstract: Cellular FLICE (FADD-like IL-1beta-converting enzyme)-inhibitory protein (c-FLIP) is a major resistance factor and critical anti-apoptotic regulator that inhibits tumor necrosis factor-alpha (TNF-alpha), Fas-L, and TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis as well as chemotherapy-triggered apoptosis in malignant cells. c-FLIP is expressed as long (c-FLIP ), short (c-FLIP ), and c-FLIP splice variants in human L S R cells. c-FLIP binds to FADD and/or caspase-8 or -10 in a ligand-dependent and-independent fashion, which in turn preven