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HA14-1, but not the BH3 mimetic ABT-737, causes Ca2+ dysregulation in platelets and human cell lines

Tijdschriftbijdrage - Tijdschriftartikel

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.
Tijdschrift: HAEMATOLOGICA
ISSN: 0390-6078
Issue: 4
Volume: 98
Pagina's: E49 - E51
Jaar van publicatie:2013
BOF-keylabel:ja
IOF-keylabel:ja
BOF-publication weight:3
CSS-citation score:1
Authors from:Higher Education