The Ca channel blocker flunarizine induces caspase-10-dependent apoptosis in Jurkat T-leukemia cells

Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, B3H 1X5, Canada.
Apoptosis (Impact Factor: 3.61). 05/2010; 15(5):597-607. DOI: 10.1007/s10495-010-0454-3
Source: PubMed

ABSTRACT Flunarizine is a Ca(2+) channel blocker that can be either cytoprotective or cytotoxic, depending on the cell type that is being examined. We show here that flunarizine was cytotoxic for Jurkat T-leukemia cells, as well as for other hematological maligancies, but not for breast or colon carcinoma cells. Treatment of Jurkat cells with flunarizine resulted in caspase-3 activation, poly (ADP-ribose) polymerase cleavage, and laddering of DNA fragments, all of which are hallmarks of apoptosis. Flunarizine-induced DNA fragmentation was inhibited by the caspase-3 inhibitor z-DEVD-fmk, the caspase-8/caspase-10 inhibitor z-IETD-fmk, and the caspase-10 inhibitor z-AEVD-fmk, but was not reduced in caspase-8-deficient Jurkat cells, indicating the involvement of caspase-10 upstream of caspase-3 activation. Interestingly, FADD recruitment to a death receptor was not involved since flunarizine caused DNA fragmentation in FADD-deficient Jurkat cells. Flunarizine treatment of Jurkat cells also resulted in reactive oxygen species production, dissipation of mitochondrial transmembrane potential, release of cytochrome c from mitochondria, and caspase-9 activation, although none of these events were necessary for apoptosis induction. Collectively, these findings indicate that flunarizine triggers apoptosis in Jurkat cells via FADD-independent activation of caspase-10. Flunarizine warrants further investigation as a potential anti-cancer agent for the treatment of hematological malignancies.

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    • "able to activate directly caspases as has been demonstrated earlier [36] [47]. Another evidence for caspase-10 dependency with no or only less involvement of FADD-adaptor protein has been described recently for another chemical but with the same set of Jurkat cells [53]. This group found the same total inhibition of all effects by the caspase-10 inhibitor zAEVDfmk and no reduction in caspase-8-deficient cells. "
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