A novel aminosteroid of the 5α-androstane-3α,17β-diol family induces cell cycle arrest and apoptosis in human promyelocytic leukemia HL-60 cells
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RM, a novel aminosteroid synthesized by our research group, shows a broad spectrum of antitumor activity against nine cancer cell lines and limited toxicity against two normal cell lines. However, its related mechanism of action has not yet been elucidated. In this study, we investigated the cellular and molecular events underlying the cytotoxicity of RM in human acute promyelocytic leukemia HL-60 cells. RM was found to induce a G0/G1 cell cycle block of HL-60 cells but not terminal myeloid differentiation. Interestingly, typical apoptotic morphological changes were exhibited by HL-60 cells treated with RM stained with Hoechst 33342 and examined by fluorescence microscopy. Apoptotic death assay using annexin-V/propidium iodide dual staining flow cytometry demonstrated a dose-dependent apoptotic effect of RM on HL-60 cells. In addition, RM induced the cleavage of caspase-3, caspase-8 and PARP, but not the cleavage of caspase-9. Our findings suggest that RM reduces HL-60 cells survival through a caspase-dependent death receptor pathway.
KeywordsAminosteroid HL-60 cells Leukemia Cell cycle Apoptosis Caspase
This work was supported by the Canadian Institutes of Health Research (CIHR) and the Canadian Cancer Research Society (CRS). The authors would like to thank Dr. Charles Doillon, Dr. Fawzi Aoudjit, Dr. Maurice Dufour and Jean-François St-Laurent for their technical assistance and their helpful discussions. Careful reading of the manuscript by Mrs. Micheline Harvey is also greatly appreciated.
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