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

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.

Dual inhibition of Mcl-1 by the combination of carfilzomib and TG02 in multiple myeloma

“…Inhibition of Mcl-1 translation has been previously demonstrated as a means to induce cell death in tumor cells. [38][39][40] To verify that Mcl-1 is the key target in the combination treatment we created cells that over express the anti-apoptotic proteins. Overexpression of Mcl-1 in RPMI-8226 cells confers significantly less protection compared to over expression of Bcl-x L .…”

Anti-Tumor Effects of the Polysaccharide Isolated from Tarphochlamys Affinis in H22 Tumor-Bearing Mice

“…where L a and L b represent the largest diameter and the smallest diameter, respectively [20,21]. At the final stage of the experiment, blood samples were collected, and serum was separated for the detection of IL-2, IL-6, IFN-γ, TNF-α and blood physiochemical assays.…”

Antitumor activity of tatariside F isolated from roots of Fagopyrum tataricum (L.) Gaertn against H22 hepatocellular carcinoma via up-regulation of p53

“…Mice were observed for 15 days, and tumor sizes were 115 measured at 6, 8, 10, 12, and 14 days after the tumor inocula-116 tion. Tumor diameters were determined by using a vernier caliper, 117 and subsequently tumor volumes were calculated as the formula: 118 Volume = (width 2 × length)/2 (Zhou et al, 2013). Mice were sacri-119 ficed immediately after 15 days, and tumors tissues were collected 120 and homogenized for further analysis.…”