Reversal effect of nimodipine on cytarabine-resistant HL60 cells associated with triggering apoptosis

Intrinsic or acquired drug resistance is the major reason for failure of cancer therapy. Multifactorial mechanisms are involved in multidrug resistance (MDR). Various arrays of drugs are indentified that sensitize multidrug–resistant cells to chemotherapy. The present study aimed to study whether nimodipine (NMDP) could reverse MDR and what mechanism is involved in the reversal effect. Cytarabine (Ara-c)-resistant HL60 leukemia cells (HL60/Ara-c) were treated with free Ara-c, free NMDP or combination of Ara-c with NMDP. The apoptotic effects were enhanced with increase of concentration, showing a dose-dependent manner. Combination of Ara-c with NMDP arrest more cells in G0/G1 phase. Bcl-2 mRNA and protein expression significantly decreased in co-administration group, while that of Bax increased. The activity of caspase-3 was remarkably activated by combination of Ara-c with NMDP, which was correlated with modulating Bcl-2/Bax. Intracellular Ca2+ concentration was significantly increased over culture time in co-administration group. In the xenograft model, antitumor activity of NMDP with Ara-c was signifanctly enhanced. In conclusion, the reversal effect of NMDP on HL60/Ara-c cells is associated with modulating proapoptotic and antiapoptotic protein expression changes and initiating a cascade of caspase activation. Combination of anticancer agents with a modulator may provide a novel strategy for improving the chemotherapeutic effects.   Key words:  Nimodipine, cytarabine, multidrug resistance, leukemia.