Triterpene derivatives and their reversing activity against multidrug resistant cancer cells

One of the major problems of cancer chemotherapy is intrinsic or acquired drug resistance. Multiple drug resistance (MDR) in cancer cells is due to the overexpression of P-glycoprotein (P-gp) in the plasma membrane of resistant cells, which mediates the efflux of MDR drugs, reducing intracellular accumulation of anticancer drugs. Therefore, searching to overcome drug resistance has been a major effort in clinical oncology. During a continuing search for plant-derived MDR-reversing agents from natural sources, Betula platyphylla var. japonica was found to potentiate the activities of anticancer drugs in multidrug-resistant KB-C2 cells at non-toxic concentrations. Bioassay-guided fractionation has resulted in the isolation of several triterpenes. It was shown that some of isolated triterpenes reversed the cytotoxicity of colchicine against KB-C2 cells. Methyl papyriferate (1) showed a potent activity which at 8.1µM was comparable to 5µM verapamil. MDR-reversing active triterpenes were shown to inhibit P-gp function. In addition, methyl papyriferate increased P-gp ATPase activity, and some MDR-reversing active triterpenes showed a weak inhibitory activity against P-gp ATPase. Based on this result, we have also prepared some derivatives of papyriferic acid to develop more potent MDR-reversing active drugs.

References: 1. Kashiwada, Y. et al. (2007)J. Nat. Prod. 70: 623–627.

2. Sekiya, M. et al. (2007) Planta Med. 73: 1558–1562.