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ABT‐199 (Venetoclax), a BH3‐mimetic Bcl‐2 inhibitor, does not cause Ca 2+ ‐signalling dysregulation or toxicity in pancreatic acinar cells
Author(s) -
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
Publication year - 2019
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14505
Subject(s) - venetoclax , programmed cell death , pancreatic cancer , intracellular , apoptosis , cancer research , cancer cell , bystander effect , pharmacology , cytosol , cancer , biology , medicine , chronic lymphocytic leukemia , immunology , microbiology and biotechnology , leukemia , biochemistry , enzyme
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 2+ 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 2+ 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.