Background and Purpose
Many cancer cells depend on anti‐apoptotic B‐cell lymphoma 2 (Bcl‐2) proteins for their survival. Bcl‐2 antagonism through Bcl‐2 homology 3 (BH3) mimetics has emerged as a novel anti‐cancer therapy. ABT‐199 (Venetoclax), a recently developed BH3 mimetic that selectively inhibits Bcl‐2, was introduced into the clinic for treatment of relapsed chronic lymphocytic leukaemia. Early generations of Bcl‐2 inhibitors evoked sustained Ca2+ responses in pancreatic acinar cells (PACs) inducing cell death. Therefore, BH3 mimetics could potentially be toxic for the pancreas when used to treat cancer. Although ABT‐199 was shown to kill Bcl‐2‐dependent cancer cells without affecting intracellular Ca2+ signalling, its effects on PACs have not yet been determined. Hence, it is essential and timely to assess whether this recently approved anti‐leukaemic drug might potentially have pancreatotoxic effects.
Single‐cell Ca2+ measurements and cell death analysis were performed on isolated mouse PACs.
Inhibition of Bcl‐2 via ABT‐199 did not elicit intracellular Ca2+ signalling on its own or potentiate Ca2+ signalling induced by physiological/pathophysiological stimuli in PACs. Although ABT‐199 did not affect cell death in PACs, under conditions that killed ABT‐199‐sensitive cancer cells, cytosolic Ca2+ extrusion was slightly enhanced in the presence of ABT‐199. In contrast, inhibition of Bcl‐xL potentiated pathophysiological Ca2+ responses in PACs, without exacerbating cell death.
Conclusion and Implications
Our results demonstrate that apart from having a modest effect on cytosolic Ca2+ extrusion, ABT‐199 does not substantially alter intracellular Ca2+ homeostasis in normal PACs and should be safe for the pancreas during cancer treatment.
This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc