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Cell Death Dis. 2013 Feb 28;4:e515. doi: 10.1038/cddis.2013.41.

Downregulation of Mcl-1 through inhibition of translation contributes to benzyl isothiocyanate-induced cell cycle arrest and apoptosis in human leukemia cells.

Author information

1
Department of Pharmacognosy, School of Pharmacy, 3rd Military Medical University, Chongqing, China.

Abstract

Benzyl isothiocyanate (BITC) is one of the compounds of ITCs' family that has attracted a great deal of interest because of its ability to exhibit anticancer activity. In this study, we investigated the effects of BITC on cell cycle arrest and apoptosis in human leukemia cell lines, primary leukemia cells, and nude mice Jurkat xenograft. Exposure of Jurkat cells to BITC resulted in dose- and time-dependent increase in apoptosis, caspase activation, cytochrome c release, nuclear apoptosis-inducing factor (AIF) accumulation, Bcl2-associated X protein (Bax) translocation, and myeloid cell leukemia-1 (Mcl-1) downregulation. Treatment with these cells also resulted in cell cycle arrest at the G2/M phase. The G2/M-arrested cells are more sensitive to undergoing Mcl-1 downregulation and apoptosis mediated by BITC. BITC downregulates Mcl-1 expression through inhibition of translation, rather than through a transcriptional, post-translational, or caspase-dependent mechanism. Dephosphorylation of eukaryotic initiation factor 4G could contribute to the inhibition of Mcl-1 translation mediated by BITC. Furthermore, ectopic expression of Mcl-1 substantially attenuates BITC-mediated lethality in these cells, whereas knockdown of Mcl-1 through small interfering RNA significantly enhances BITC-mediated lethality. Finally, administration of BITC markedly inhibited tumor growth and induced apoptosis in Jurkat xenograft model in association with the downregulation of Mcl-1. Taken together, these findings represent a novel mechanism by which agents targeting Mcl-1 potentiate BITC lethality in transformed and primary human leukemia cells and inhibitory activity of tumor growth of Jurkat xenograft model.

PMID:
23449451
PMCID:
PMC3734843
DOI:
10.1038/cddis.2013.41
[Indexed for MEDLINE]
Free PMC Article

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