ABT-199 (Venetoclax), a BH3-mimetic Bcl-2 inhibitor, does not cause Ca2+ -signalling dysregulation or toxicity in pancreatic acinar cells

Abstract

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.

Experimental approach: Single-cell Ca²⁺ measurements and cell death analysis were performed on isolated mouse PACs.

Key results: 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.

Linked articles: 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.