Abstract
P-glycoprotein-mediated drug efflux can yield a multidrug-resistance (MDR) phenotype that is associated with a poor response to cancer chemotherapy. Development of safe and effective MDR-reversing agents is an important approach in the clinic. The aim of this study was to observe the effects of CJX2, an amlodipine derivative, on the inhibition of P-gp function and P-gp-mediated MDR in K562/DOX cells and parental K562 cells. Based on the flow cytometric technology, the uptake, accumulation, and efflux of rhodamine123 (Rh123) were detected in these cells by measuring Rh123-associated mean fluorescence intensity (MFI). The effects of CJX2 on the doxorubicin cytotoxicity were evaluated by assaying for MTT (3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide) reduction and the reversal fold (RF) values. The DNA content, percentage of apoptosis, and cell cycle analysis were monitored with flow cytometry. Intracellular accumulation of doxorubicin was also assessed by the determination of doxorubicin-associated MFI. Verapamil was employed as a comparative agent. Incubation of K562/DOX cells with CJX2 caused a marked increase in accumulation, uptake, and a notable decrease in efflux of Rh123. No such results were found in parental K562 cells. The inhibitory effect of the agent on P-gp function was reversible, but it persisted at least for 90 min after removal of 2.5 µM CJX2 from incubation medium. The doxorubicin-induced cytotoxicity, apoptosis, and cell cycle perturbations were significantly potentiated by CJX2. The intracellular accumulation of doxorubicin was enhanced in the presence of various concentrations of CJX2. The CJX2 exhibited potent effects in vitro in the reversal of P-gp-mediated MDR, suggesting that the compound may become a candidate for an effective MDR-reversing agent in cancer chemotherapy. Drug Dev. Res. 66:278–285, 2006. © 2006 Wiley-Liss, Inc.
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