Inhibition of P-glycoprotein and multidrug resistance protein 1 by dietary phytochemicals.
OBJECTIVE
For the development of a safe and effective dual inhibitor of anticancer drug efflux transporters P-glycoprotein and multidrug resistance protein 1 (MRP1) to conquer multidrug resistance, we investigated the effects of dietary phytochemicals on the functions of P-glycoprotein and MRP1.


METHODS
The effects of dietary phytochemicals on the functions of P-glycoprotein and MRP1 were investigated using P-glycoprotein-overexpressing human carcinoma KB-C2 cells and human MRP1 gene-transfected KB/MRP cells. The effects of natural compounds found in dietary supplements, herbs, and foods such as sesame, ginkgo, soybean, and licorice were evaluated.


RESULTS
The accumulation of daunorubicin, a fluorescent substrate of P-glycoprotein, increased in the presence of sesamin, ginkgolic acid, matairesinol, glycyrrhetinic acid, glabridin, and phyllodulcin in KB-C2 cells. Glycyrrhetinic acid and matairesinol also increased the accumulation of calcein, a fluorescent substrate of MRP1, in KB/MRP cells. KB-C2 and KB/MRP cells were sensitized to anticancer drugs by glycyrrhetinic acid, showing that glycyrrhetinic acid reverses multidrug resistance. The verapamil-stimulated P-glycoprotein ATPase activity was inhibited by glycyrrhetinic acid. Glycyrrhetinic acid stimulated the ATPase activity of MRP1.


CONCLUSIONS
These results suggest that dietary phytochemicals, such as glycyrrhetinic acid found in licorice, have dual inhibitory effects on P-glycoprotein and MRP1 and might become useful to enhance the efficacy of cancer chemotherapy.
Nabekura
Tomohiro
T
Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Higashi-jima, Akiha-ku, Niigata 956-8603, Japan. nabe@nupals.ac.jp
Yamaki
Takeshi
T
Ueno
Kazuyuki
K
Kitagawa
Shuji
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D003630:Daunorubicin / Q000378:metabolism; D004032:Diet; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005419:Flavonoids / Q000494:pharmacology*; D005452:Fluoresceins / Q000378:metabolism; D006034:Glycyrrhetinic Acid / Q000494:pharmacology; D006801:Humans; D007624:KB Cells; D010944:Plants / Q000737:chemistry*; D014747:Vinblastine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D005419:Flavonoids; D005452:Fluoresceins; D014747:Vinblastine; D004317:Doxorubicin; D000251:Adenosine Triphosphatases; D006034:Glycyrrhetinic Acid; C007740:fluorexon; D003630:Daunorubicin