Regulated cell death pathways: new twists in modulation of BCL2 family function

A number of cell death pathways have been recognized. Though apoptosis and autophagy have been well characterized, programmed necrosis has recently received attention and may provide clinical alternatives to suppress resistant tumors. Necrosis is primarily characterized by large-scale permeabilization, swelling, and rupture of cell membranes and the release of pro-inflammatory cytokines. Traditionally, necrosis in cancer cells has been indicative of poor prognoses, as chronic inflammation was found to encourage tumor growth. Yet, many antitumor effects associated with necrosis have been discovered in certain settings, such as the formation of an effective antitumor immune response. In this way, finding ways to attenuate the pro-tumor effects of necrosis while engaging the antitumor pathways via drugs, radiation, and sensitization may prove valuable as a clinical focus for the future. We hypothesize that the use of Bcl-2 inhibitors may enhance necrotic death characterized by inflammation and antitumor immunity. In this article, we briefly review apoptosis and autophagy and reason how necrosis may be a suitable alternative therapeutic endpoint. We then highlight novel inhibitors of Bcl-2 that may provide clinical application of our hypothesis in the future.