Pharmacological targeting of c-FLIPL and Bcl-2 family members promotes apoptosis in CD95L-resistant cells

Abstract

The development of efficient combinatorial treatments is one of the key tasks in modern anti-cancer therapies. An apoptotic signal can either be induced by activation of death receptors (DR) (extrinsic pathway) or via the mitochondria (intrinsic pathway). Cancer cells are characterized by deregulation of both pathways. Procaspase-8 activation in extrinsic apoptosis is controlled by c-FLIP proteins. We have recently reported the small molecules FLIPinB/FLIPinBγ targeting c-FLIPL in the caspase-8/c-FLIPL heterodimer. These small molecules enhanced caspase-8 activity in the death-inducing signaling complex (DISC), CD95L/TRAIL-induced caspase-3/7 activation and subsequent apoptosis. In this study to increase the pro-apoptotic effects of FLIPinB/FLIPinBγ and enhance its therapeutic potential we investigated costimulatory effects of FLIPinB/FLIPinBγ in combination with the pharmacological inhibitors of the anti-apoptotic Bcl-2 family members such as ABT-263 and S63845. The combination of these inhibitors together with FLIPinB/FLIPinBγ increased CD95L-induced cell viability loss, caspase activation and apoptosis. Taken together, our study suggests new approaches for the development of combinatorial anti-cancer therapies specifically targeting both intrinsic and extrinsic apoptosis pathways.

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“…Namely, the pro-apoptotic protein BAX, anti-apoptotic protein BCL-2, and apoptosis regulator of the caspase family have significant effects on cell apoptosis [39][40] . BCL-2 is proven to be the most important factor significantly inhibitings cell apoptosis [41] , and upregulated Bcl-2 gene expression can resist apoptosis-induced cell death [42] . The ratio of BCL-2 to BAX determines the opening and closing of the mitochondrial permeability pore, which promotes the release of cytochrome C from mitochondrial membrane into cytosol [43] .…”

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“…There are two main apoptosis pathways, including death receptor-mediated apoptosis pathway and mitochondria-mediated apoptosis pathway [30,31]. The death receptor pathway mainly promotes the production of caspase-8, and then activates the downstream caspase factor, thus initiating the apoptosis process dependent on the caspase-enzyme cascade [32].…”