A novel aminosteroid of the 5α-androstane-3α,17β-diol family induces cell cycle arrest and apoptosis in human promyelocytic leukemia HL-60 cells.
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.
Jegham
Hajer
H
Laboratory of Medicinal Chemistry, CHUQ (CHUL)-Research Center (Endocrinology and Genomic Unit), 2705 Laurier Boulevard, Québec, Québec G1V 4G2, Canada.
Roy
Jenny
J
Maltais
René
R
Desnoyers
Serge
S
Poirier
Donald
D
D015113:Androstane-3,17-diol / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology*; D008856:Microscopy, Fluorescence; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D013997:Time Factors
D000970:Antineoplastic Agents; D015113:Androstane-3,17-diol; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases