Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCB119

Poster Communications

Selective inhibition of Bcl-2 by venetoclax (ABT-199) does not induce intracellular Ca2+ responses or cell death in pancreatic acinar cells

M. A. Jakubowska1,2, G. Bultynck3, J. V. Gerasimenko1, O. V. Gerasimenko1, O. H. Petersen1, T. Vervliet3, P. E. Ferdek1,4

1. School of Biosciences, Cardiff University, Cardiff, Wales, United Kingdom. 2. International Associated Laboratory (LIA), Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland. 3. Laboratory of Molecular and Cellular Signaling, KU Leuven, Leuven, Belgium. 4. Department of Cell Biology, Jagiellonian University, Krakow, Poland.

Many cancer cells depend on the mitochondrial function of anti-apoptotic B cell lymphoma 2 (Bcl-2) proteins for their survival. Therefore Bcl-2 antagonism through BH3 mimetics emerged as a precision anti-cancer therapy. We previously showed that early Bcl-2 inhibitors BH3I-2' and HA14-1 elicit sustained Ca2+ responses in pancreatic acinar cells (PACs) inducing not only apoptosis but also cell necrosis. Because of this, BH3 mimetics could potentially be toxic for the pancreas when used to treat cancer. Venetoclax (ABT-199) is a recently developed selective Bcl-2 inhibitor which was introduced into the clinic for the treatment of relapsed chronic lymphocytic leukaemia patients. Although Venetoclax was shown to kill Bcl-2-dependent cancer cells without affecting intracellular Ca2+ signalling, its effects on PACs have not yet been determined. Therefore, it becomes essential and timely to assess whether the recently approved anti-leukemic drug might have potentially pancreatotoxic effects. In this study single-cell real-time Ca2+ measurements and cell death analysis were performed on freshly isolated mouse PACs. We show here that selective inhibition of Bcl-2 via ABT-199 neither elicited intracellular Ca2+ signalling on its own nor altered Ca2+ signalling induced by physiological/pathophysiological stimuli in PACs. Also, cell death was mostly unaffected by ABT-199. In contrast, selective inhibition of Bcl-XL or inhibition of multiple anti-apoptotic Bcl-2 family proteins potentiated pathophysiological Ca2+ responses in PACs, but without exacerbating cell death. Selective inhibition of either Bcl-2 or Bcl-XL provided a modest protective effect against cell death induced by menadione. In conclusion, our results demonstrate that ABT-199 does not alter intracellular Ca2+ homeostasis in normal PACs and thus should be safe for the pancreas when used for treating cancer.

Where applicable, experiments conform with Society ethical requirements