Chabamide induces cell cycle arrest and apoptosis by the Akt/MAPK pathway and inhibition of P-glycoprotein in K562/ADR cells

Jie Ren, Yuanyuan Xu, Qianhui Huang, Jie Yang, Meng Yang, Kun Hu, Kun Wei
Anti-cancer Drugs 2015, 26 (5): 498-507
One of the major mechanisms of multidrug resistance in cancer therapy is the overexpression of P-glycoprotein (P-gp). Chabamide, a dimeric alkaloid isolated from Piper chaba Hunter, shows antimalarial, antituberculosis, and cytotoxic activities. However, its mechanism of action has not been elucidated. In this study, the molecular mechanism underlying the cytotoxicity and downregulation of P-gp expression by chabamide in adriamycin-resistant human leukemia cells (K562/ADR) was clarified. Results show that chabamide inhibited the growth of K562/ADR cells in a dose-dependent and time-dependent manner, and significantly inhibited cell proliferation by cell cycle arrest in the G0/G1 phase, which was associated with an obvious increase in p21 and decrease in cyclin D1 and CDK2/4/6 protein expression. Moreover, chabamide could regulate the changes in the mitochondrial membrane potential, increase the expression of apoptosis-related proteins, such as Bax and cytochrome c, and decrease the protein expression levels of Bcl-2, caspase-9, caspase-3, PARP-1, and p-Akt. In addition, we found that JNK, ERK1/2, and p38 were regulated by chabamide in K562/ADR cells. Further studies indicated that the decrease in the reactive oxygen species level inhibited intrinsic P-gp expression. Therefore, chabamide-induced apoptosis in K562/ADR cells was associated with Akt/MAPK and the inhibition of P-gp. These results provide a biochemical basis for possible clinical applications of chabamide in the treatment of leukemia.

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