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, (+)-»ans-3-(3, 4-dimethoxyphenyl)- 4-[(E)-3,4-dimethoxystyryl]cyclohex-1-ene (1), exhibited highly potent P-gp inhibitory activity, decreasing the IC₅₀ value of daunomycin (DNM) to 4.31 + 0.40 hm in the cells (DNM IC₅₀ = 37.1 + 0.59 hm). The positive control, verapamil decreased the IC₅₀ value of DNM to 6.94 + 0.40 |Im. Three phenylbutenoid monomers, 24 from this plant, also resulted in a significant decrease in the IC₅₀ values of DNM compared with the control. In particular, compound 1 markedly enhanced [ ³H]-DNM accumulation and significantly reduced [³H]-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.