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

Abstract

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.

P-glycoprotein inhibitors of natural origin as potential tumor chemo-sensitizers: A review

“…Finally, the literature found regarding the P-gp inhibition by natural products was too much to be covered in one review article, therefore the current review focused only on major classes of naturally occurring compounds. However, several reports were found concerning the activity of various plant extracts [118] and their constituents as P-gp inhibitors; viz., anthraquinones [119] , phenylbutanoids [120] , phytosterols [121] , cannabinoids [122] , carotenoids [123] , curcumenoids [124] , volatile oils [125] , sulfur compounds [126] , and polyacetylenes. [127] In addition, some vitamins such as vitamin D revealed significant reversal of multi-drug resistance in many resistant cells [128] .…”

Natural Products as Alternative Choices for P-Glycoprotein (P-gp) Inhibition

“…Gomisin and Pregomisin, the lignans, shows MDR reversal phenomena on human HepG2 hepatoma cell lines through uncompetitive inhibition of P-gp-ATPase activity and alters P-gp substrate interactions [ 245 ]. Phenylbutanoid inhibits P-gp mediated MDR expression and promotess daunomycin uptake in breast cancer cells (MCF-7/Adr) [ 246 ].…”

Phytochemicals and Bioactivities of Zingiber cassumunar Roxb

“…The extracts and constituents of Z. cassumunar have diverse bioactivities, including antioxidant [21,[26][27][28], anti-inflammatory [7,9,12,19,23,[29][30][31][32][33][34][35][36][37][38][39], anticancer [8,13,15,[40][41][42][43][44][45][46][47][48], neuroprotective/neurotrophic [14,19,20], cosmeceutical [17,21], and antifungal/antibacterial [22][23][24] activities. Although there has been a review of the clinical effects of various formulations using Plai (Z. cassumunar) on were pain relief, acne treatment, and antihistamine [1], there has been no previous report summarizing the accumulated studies in the literature on the phytochemicals and in vitro and in vivo biological properties of Z. cassumunar, including our previous studies that have contributed to discovering the chemical diversity and biological activities of this plant [8,9,15,…”