Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Pharmacology & Pharmacy, ANTI-APOPTOTIC BCL-2, ACUTE LYMPHOBLASTIC-LEUKEMIA, BH3 MIMETIC ABT-737, ENDOPLASMIC-RETICULUM, CONCISE GUIDE, INOSITOL 1,4,5-TRISPHOSPHATE, CALCIUM-RELEASE, CA2+ RELEASE, RECEPTOR, CANCER, Acinar Cells, Animals, Antineoplastic Agents, Bridged Bicyclo Compounds, Heterocyclic, Calcium Signaling, Male, Mice, Inbred C57BL, Pancreas, Peptide Fragments, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Sulfonamides, ABT-199/Venetoclax, BH3 mimetic, Bcl-2, Ca2+ signalling, cell death, pancreatic acinar cells, C14/19/099#55221880, 1115 Pharmacology and Pharmaceutical Sciences, 3214 Pharmacology and pharmaceutical sciences

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.