Nabekura Tomohiro, Yamaki Takeshi, Ueno Kazuyuki, Kitagawa Shuji
Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Higashi-jima, Akiha-ku, Niigata 956-8603, Japan.
Cancer Chemother Pharmacol. 2008 Oct;62(5):867-73. doi: 10.1007/s00280-007-0676-4. Epub 2008 Jan 19.
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.
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.
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.
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.
为开发一种安全有效的抗癌药物外排转运蛋白P-糖蛋白和多药耐药蛋白1（MRP1）双重抑制剂以克服多药耐药性，我们研究了膳食植物化学物质对P-糖蛋白和MRP1功能的影响。
使用过表达P-糖蛋白的人癌细胞KB-C2细胞和转染了人MRP1基因的KB/MRP细胞，研究膳食植物化学物质对P-糖蛋白和MRP1功能的影响。评估了膳食补充剂、草药和食物（如芝麻、银杏、大豆和甘草）中天然化合物的作用。
在KB-C2细胞中，芝麻素、银杏酸、罗汉松脂素、甘草次酸、光甘草定和根皮苷存在时，P-糖蛋白的荧光底物柔红霉素的积累增加。甘草次酸和罗汉松脂素也增加了KB/MRP细胞中MRP1的荧光底物钙黄绿素的积累。甘草次酸使KB-C2和KB/MRP细胞对抗癌药物敏感，表明甘草次酸可逆转多药耐药性。甘草次酸抑制维拉帕米刺激的P-糖蛋白ATP酶活性。甘草次酸刺激MRP1的ATP酶活性。
这些结果表明，膳食植物化学物质，如甘草中的甘草次酸，对P-糖蛋白和MRP1具有双重抑制作用，可能有助于提高癌症化疗的疗效。
