Potent modulation of P-glycoprotein activity by naturally occurring phenylbutenoids from Zingiber cassumunar

Five phenylbutenoid derivatives from the rhizomes of Zingiber cassumunar Roxb. (Zingiberaceae) were evaluated for their P-glycoprotein (P-gp) inhibitory effects in a P-gp over-expressing multidrug resistant (MDR) human breast cancer cell line, MCF-7/ADR. As a result, a phenylbutenoid dimer, (+/-)-trans-3-(3,4-dimethoxyphenyl)-4-[(E)-3,4-dimethoxystyryl]cyclohex-1-ene (1), exhibited highly potent P-gp inhibitory activity, decreasing the IC(50) value of daunomycin (DNM) to 4.31 +/- 0.40 microm in the cells (DNM IC(50) = 37.1 +/- 0.59 microm). The positive control, verapamil decreased the IC(50) value of DNM to 6.94 +/- 0.40 microm. Three phenylbutenoid monomers, 2-4 from this plant, also resulted in a significant decrease in the IC(50) values of DNM compared with the control. In particular, compound 1 markedly enhanced [(3)H]-DNM accumulation and significantly reduced [(3)H]-DNM efflux compared with the control, and this effect was more potent than that of verapamil, a well-known P-gp inhibitor. These results suggest that compound 1 of Z. cassumunar can be developed as a potent chemo-sensitizing agent that reverses P-gp-mediated MDR in human cancer chemotherapy.