Vibsanin A combined with tyrosine kinase inhibitors induces HL-60 cell differentiation by down-regulating c-Myc expression / 国际药学研究杂志

ABSTRACT

Objective: To explore the molecular mechanisms underlying the acute myeloid leukemia(AML)HL-60 cell differentiation induced by natural compound vibsanin A combined with tyrosine kinase inhibitors(TKI). Methods: Cell surface marker CD11b expression was detected by flow cytometry in HL-60 cells after treatment of the cells with vibsanin A in combination with imatinib or saracatinib for 72 h,and the cell morphology was examined by Wrigh-Giemsa staining. qRT-PCR and Western blot were used to examine the expression of differentiation-related C/EBPα,C/EBPβ, and c-Myc at both mRNA and protein levels in HL-60 cells after the cells were treated with the two drug combinations for various time(0-24 h). The recombinant lentiviral vector expressing c-Myc was constructed and used to transfect HL-60 cells in which the c-Myc cDNA was ectopically over expressed. The effect of c-Myc expression on the HL-60 cell differen-tiation induced by vibsanin A combined with TKI was investigated using the transfected HL-60 cells. Results: Vibsanin A combined with imatinib or saracatinib significantly enhanced HL-60 cell differentiation. Both drug combinations downregulated the expression of c-Myc at both mRNA and protein levels(P<0.01)in the HL-60 cells. In the transfected HL60 cells,the ectopic c-Myc overexpression could significantly counteract the down-regulated c-Myc expression and inhibit the cell differentiation induced by the vibsanin A/TKI combination. Conclusion: The combination of vibsanin A with imatinib or saracatinib could induce the HL-60 cell differentiation,probably via the downregulation of c-Myc expression