Effects of dietary chemopreventive phytochemicals on P-glycoprotein function

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Abstract

The effects of dietary phytochemicals on P-glycoprotein function were investigated using human multidrug-resistant carcinoma KB-C2 cells and the fluorescent P-glycoprotein substrates daunorubicin and rhodamine 123. The effects of natural chemopreventive compounds, capsaicin found in chilli peppers, curcumin in turmeric, [6]-gingerol in ginger, resveratrol in grapes, sulforaphane in broccoli, 6-methylsulfinyl hexyl isothiocyanate (6-HITC) in Japanese horseradish wasabi, indole-3-carbinol (I3C) in cabbage, and diallyl sulfide and diallyl trisulfide in garlic, were examined. The accumulation of daunorubicin in KB-C2 cells increased in the presence of capsaicin, curcumin, [6]-gingerol, and resveratrol in a concentration-dependent manner. The accumulation of rhodamine 123 in KB-C2 cells was also increased, and the efflux of rhodamine 123 from KB-C2 cells was decreased by these phytochemicals. Sulforaphane, 6-HITC, I3C, and diallyl sulfide and diallyl trisulfide had no effect. These results suggest that dietary phytochemicals, such as capsaicin, curcumin, [6]-gingerol, and resveratrol, have inhibitory effects on P-glycoprotein and potencies to cause drug–food interactions.

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Materials and methods

Materials. Dulbecco’s modified Eagle’s medium (D-MEM) and fetal bovine serum (FBS) were purchased from Invitrogen (Carlsbad, CA). Colchicine, daunorubicin, rhodamine 123, vinblastine, capsaicin, and [6]-gingerol were from Wako Pure Chemical Industries (Osaka, Japan). Curcumin, resveratrol, and indole-3-carbinol (I3C) were from Sigma Chemical (St. Louis, MO). Sulforaphane, 6-methylsulfinyl hexyl isothyocyanate (6-HITC), diallyl sulfide, and diallyl trisulfide were from LKT Laboratories (St.

Effects of phytochemicals on daunorubicin accumulation

Fig. 2 shows the accumulation ratio of daunorubicin in KB-C2 cells in the presence of 50 μM dietary phytochemicals. Capsaicin, curcumin, [6]-gingerol, and resveratrol increased the cellular accumulation of daunorubicin, which indicates that these phytochemicals inhibit the P-gp-mediated efflux of daunorubicin. In contrast, sulforaphane, 6-HITC, I3C, diallyl sulfide, and diallyl trisulfide had no effects on the cellular accumulation of daunorubicin. Higher concentrations (100 μM) of sulforaphane,

Discussion

Over the last few years, the effects of natural products in cancer treatment or prevention have been extensively studied. Tea (Camellia sinensis) consumption has been shown to inhibit tumor formation at different organ sites including the skin, oral cavity, esophagus, stomach, intestine, lung, liver, pancreas, mammary gland, urinary bladder, and prostate [6], [7]. (−)-Epigallocatechin gallate (EGCG), a major water-extractable constituent of tea, has been presumed to be the active compound for

Acknowledgments

This work was supported by a Grant-in-Aid for the Encouragement of Young Scientists from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a Sasakawa Scientific Research Grant from the Japan Science Society, and The Danone Institute of Japan, The 2004 DIJ Research Grant (T.N.), and a grant from the Promotion and Mutual Aid Corporation for Private Schools in Japan.

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