On BH3 Mimetics and Ca²⁺ Signaling

Preclinical Research 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 Ca²⁺ homeostasis, including Ca²⁺ release from the intracellular stores as well as Ca²⁺ 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 Ca²⁺ signals. Indeed, it has been reported that some BH3 mimetics release Ca²⁺ from the intracellular stores causing Ca²⁺ overload in the cytosol. Therefore, the effects of any new BH3 mimetics on cellular Ca²⁺ homeostasis should be tested before these compounds progress to clinical trials. Drug Dev Res 78 : 313-318, 2017. © 2017 Wiley Periodicals, Inc.