DISC construction promotes the autocleavage and activation of caspase 8, resulting in apoptotic death that is eventually driven by further activation of the effector caspases. Mobile FLICE inhibitory protein is a truncated form of caspase 8 that lacks enzymatic activity. Thus, c FLIP acts as a important inhibitor of TRAIL/death receptor induced apoptosis. c Mitochondrion FLIP has numerous splice variants, nevertheless, only two of these have been well characterized at the protein levels: the 26 kDa small form containing two death effector domains and the 55 kDa long form containing an inactive caspase like area along with the two death effector domains. Although cancer cells possess innate resistance to TRAIL, many anticancer agents may sensitize cancer cells to TRAIL induced apoptosis through various mechanisms such as induction of DR5 and/or DR4 expression and/or downregulation of c FLIP levels. Akt has been suggested to positively control c FLIP expression because activation or suppression of Akt accordingly increased or decreased the quantities of c FLIP. Recently, Akt1 was shown to specifically communicate with FLIPL and to phosphorylate it at S273, ultimately causing stabilization of FLIPL. Ergo, the present study Cyclopamine clinical trial mainly focused on determining whether API 1 negatively regulates c FLIP levels and sensitizes cancer cells to TRAILinduced apoptosis. Moreover, we have unmasked the mechanisms through which API 1 lowers c FLIP levels and improves TRAIL induced apoptosis. Reagents API 1 was acquired from the National Cancer Institute. API 2 was given by Dr. J. Q. Cheng. MK2206 was obtained from Active Biochem. The soluble recombinant individual TRAIL was purchased from PeproTech, Inc.. The proteasome inhibitor MG132 and the protein synthesis inhibitor cycloheximide were obtained from Sigma Chemical Co.. Monoclonal anti FLIP antibody was received from Alexis Biochemicals. Mouse monoclonal anticaspase 3 antibody was purchased from Imgenex. Rabbit polyclonal anti DR5 antibody was obtained from ProSci Inc..