Title: HA14-1, but not the BH3 mimetic ABT-737, causes Ca2+ dysregulation in platelets and human cell lines
Authors: Akl, Haidar
Vandecaetsbeek, Ilse
Monaco, Giovanni
Kauskot, Alexandre
Luyten, Tomas
Welkenhuyzen, Kirsten
Hoylaerts, Marc
De Smedt, Humbert
Parys, Jan
Bultynck, Geert # ×
Issue Date: Apr-2013
Publisher: Il Pensiero Scientifico
Series Title: Haematologica vol:98 issue:4 pages:e49-e51
Abstract: Antagonizing Bcl-2 proteins by BH3 mimetics is a promising anti-cancer strategy. Yet, this has been associated with thrombocytopenia. Dysregulation of the intracellular Ca(2+) homeostasis in platelets by ABT-737 has been implicated in this phenomenon, but the underlying mechanism is a highly controversial issue. It is important to establish whether ABT-737 affects intracellular Ca(2+) homeostasis, as this may cause general adverse effects in humans. We compared ABT-737 and HA14-1, another proposed Bcl-2 antagonist with putative SERCA-inhibitory properties. We demonstrate that HA14-1, but not ABT-737, disturbs endoplasmic reticulum Ca(2+) homeostasis in platelets. HA14-1 potently inhibited ER Ca(2+)-uptake activity of SERCA2b, while ABT-737 only displayed minor inhibitory effects on ATP-driven ER Ca(2+) uptake at concentrations well above the therapeutically relevant concentrations (10 mM and higher). Moreover, HA14-1, but not ABT-737, inhibited IP(3)-induced Ca(2+) release. Our findings indicate that the effects of ABT-737 on thrombocytopenia are not due to dysregulation of intracellular Ca(2+) homeostasis.
ISSN: 0390-6078
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Molecular and Cellular Signaling
Molecular and Vascular Biology
× corresponding author
# (joint) last author

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