Multifaceted anticancer activity of BH3 mimetics: Current evidence and future prospects
BH3 mimetics are a novel class of anticancer agents designed to specifically target pro-survival proteins of the Bcl-2 family. Like endogenous BH3-only proteins, BH3 mimetics competitively bind to surface hydrophobic grooves of pro-survival Bcl-2 family members, counteracting their protective effects and thus facilitating apoptosis in cancer cells. Among the small-molecule BH3 mimetics identified, ABT-737 and its analogs, obatoclax as well as gossypol derivatives are the best characterized. The anticancer potential of these compounds applied as a single agent or in combination with chemotherapeutic drugs is currently being evaluated in preclinical studies and in clinical trials. In spite of promising results, the actual mechanisms of their anticancer action remain to be identified. Findings from preclinical studies point to additional activities of BH3 mimetics in cancer cells that are not connected with apoptosis induction. These off-target effects involve induction of autophagy and necrotic cell death as well as modulation of the cell cycle and multiple cell signaling pathways. For the optimization and clinical implementation of BH3 mimetics, a detailed understanding of their role as inhibitors of the pro-survival Bcl-2 proteins, but also of their possible additional effects is required. This review summarizes the most representative BH3 mimetic compounds with emphasis on their off-target effects. Based on the present knowledge on the multifaceted effects of BH3 mimetics on cancer cells, the commentary outlines the potential pitfalls and highlights the considerable promise for cancer treatment with BH3 mimetics.