Details

Autor(en) / Beteiligte

• Jakubowska, Monika A
• Kerkhofs, Martijn
• Martines, Claudio
• Efremov, Dimitar G
• Gerasimenko, Julia V
• Gerasimenko, Oleg V
• Petersen, Ole H
• Bultynck, Geert
• Vervliet, Tim
• Ferdek, Pawel E

Titel

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

Ist Teil von

• British journal of pharmacology, 2019-11, Vol.176 (22), p.4402-4415

Ort / Verlag

England

Erscheinungsjahr

2019

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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 Ca 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 Ca 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 Ca measurements and cell death analysis were performed on isolated mouse PACs. Inhibition of Bcl-2 via ABT-199 did not elicit intracellular Ca signalling on its own or potentiate Ca 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 Ca extrusion was slightly enhanced in the presence of ABT-199. In contrast, inhibition of Bcl-xL potentiated pathophysiological Ca responses in PACs, without exacerbating cell death. Our results demonstrate that apart from having a modest effect on cytosolic Ca extrusion, ABT-199 does not substantially alter intracellular Ca 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.