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BH3 mimetics are small-molecule inhibitors of B-cell lymphoma-2 (Bcl-2) and Bcl-xL, which disrupt the heterodimerisation of anti- and pro-apoptotic Bcl-2 family members sensitising cells to apoptotic death. These compounds have been developed as anti-cancer agents to counteract increased levels of Bcl-2 proteins often present in cancer cells. Application of a chemotherapeutic drug supported with a BH3 mimetic has the potential to overcome drug resistance in cancers overexpressing anti-apoptotic Bcl-2 proteins and thus increase the success rate of the treatment. We have previously shown that the BH3 mimetics, BH3I-2′ and HA14-1, induce Ca 2+  release from intracellular stores followed by a sustained elevation of the cytosolic Ca 2+  concentration. Here we demonstrate that loss of Bax, but not Bcl-2 or Bak, inhibits this sustained Ca 2+  elevation. What is more, in the absence of Bax, thapsigargin-elicited responses were decreased; and in two-photon-permeabilised  bax  −/−  cells, Ca 2+  loss from the ER was reduced compared to WT cells. The Ca 2+ -like peptides, CALP-1 and CALP-3, which activate EF hand motifs of Ca 2+ -binding proteins, significantly reduced excessive Ca 2+  signals and necrosis caused by two BH3 mimetics: BH3I-2′ and gossypol. In the presence of CALP-1, cell death was shifted from necrotic towards apoptotic, whereas CALP-3 increased the proportion of live cells. Importantly, neither of the CALPs markedly affected physiological Ca 2+  signals elicited by ACh, or cholecystokinin. In conclusion, the reduction in passive ER Ca 2+  leak in  bax  −/−  cells as well as the fact that BH3 mimetics trigger substantial Ca 2+  signals by liberating Bax, indicate that Bax may regulate Ca 2+  leak channels in the ER. This study also demonstrates proof-of-principle that pre-activation of EF hand Ca 2+ -binding sites by CALPs can be used to ameliorate excessive Ca 2+  signals caused by BH3 mimetics and shift necrotic death towards apoptosis.

BH3 mimetic-elicited Ca2+ signals in pancreatic acinar cells are dependent on Bax and can be reduced by Ca2+-like peptides