On BH3 Mimetics and Ca(2+) Signaling

[Table: see text] BH3 mimetics are anticancer agents that reproduce the spatial arrangement of the BH3 domain of Bcl‐2 family proteins. Just like the BH3‐only proteins, these compounds bind to the hydrophobic cleft of the pro‐survival Bcl‐2 members such as Bcl‐2 or Bcl‐xL, and disrupt their heterodimerization with pro‐apoptotic Bax or Bak, sensitizing cells to chemotherapy. In recent years, it has become clear that Bcl‐2 family proteins are engaged in regulation of intracellular Ca(2+) homeostasis, including Ca(2+) release from the intracellular stores as well as Ca(2+) fluxes across the plasma membrane. Given that BH3 mimetics shift the balance between the prosurvival and proapoptotic Bcl‐2 members, they might indirectly exert effects on intracellular Ca(2+) signals. Indeed, it has been reported that some BH3 mimetics release Ca(2+) from the intracellular stores causing Ca(2+) overload in the cytosol. Therefore, the effects of any new BH3 mimetics on cellular Ca(2+) homeostasis should be tested before these compounds progress to clinical trials. Drug Dev Res 78 : 313–318, 2017. © 2017 Wiley Periodicals, Inc.