Endoplasmic reticulum stress associated with caspases-4 and-2 mediates korbazol-induced B-chronic lymphocytic leukemia cell apoptosis

Purpose: B-cell chronic lymphocytic leukemia (B-CLL) is an incurable disease that rapidly develops drug resistance. Therefore there is a need for identifying new agents that will improve the therapeutic outcome. Korbazol is a natural product known to exert cytotoxic effect on the in vitro survival of leukemic cells. The aim of this study was to investigate the mechanism of korbazol-induced apoptosis in B-CLL leukemic cells. Methods: Peripheral blood mononuclear cells from 10 B-CLL patients were used for assessing the effect of caspase inhibitors and chelator of intracellular Ca2+ Results: Cell death rate induced by the tested compound was decreased with the caspase-3 inhibitor Ac-DEVD-CHO, and the inhibitors of caspase-2 (Z-VDVAD-FMK) and -4 (ZYVAD-FMK), but not with the caspase-9 inhibitor z-LEHD-FMK and caspase-8 inhibitor z-IETD-FMK No significant release of cytochrome C (cyt C) from mitochondria to the cytosol of B-CLL cells treated with korbazol was observed. Moreover, chelating of intracellular Ca2+ with BAPTA-AM almost completely abolished the cytotoxic effect of korbazol. Conclusion: Engagement of caspases-2 and -4 and mobilization of intracellular Ca2+ indicate involvement of endoplasmic reticulum (ER) stress in apoptosis induced by korbazol.