Cepharanthine is a potent reversal agent for MRP7(ABCC10)-mediated multidrug resistance

• Published in: Biochemical pharmacology 2009-03, Vol.77 (6), p.993-1001
• Main Authors: Zhou, Ying, Hopper-Borge, Elizabeth, Shen, Tong, Huang, Xiao-Cong, Shi, Zhi, Kuang, Ye-Hong, Furukawa, Tatsuhiko, Akiyama, Shin-ichi, Peng, Xing-Xiang, Ashby, Charles R., Chen, Xiang, Kruh, Gary D., Chen, Zhe-Sheng
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents, Phytogenic - pharmacology; Benzylisoquinolines - chemistry; Benzylisoquinolines - pharmacology; Biological and medical sciences; Biological Transport, Active - drug effects; Biological Transport, Active - physiology; Cell Line; Cell Line, Tumor; Cepharanthine; Chemotherapy; Dose-Response Relationship, Drug; Drug Resistance, Multiple - drug effects; Drug Resistance, Multiple - physiology; E 217βG transport; Humans; MDR; Medical sciences; MRP7; Multidrug Resistance-Associated Proteins - antagonists & inhibitors; Multidrug Resistance-Associated Proteins - physiology; Paclitaxel; Paclitaxel - metabolism; Paclitaxel - pharmacology; Pharmacology. Drug treatments; Treatment. General aspects; Tumors
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2008.12.005

Multidrug resistance protein 7 (MRP7; ABCC10) is an ABC transporter that confers resistance to anticancer agents such as the taxanes. We previously reported that several inhibitors of P-gp and MRP1 were able to inhibit the in vitro transport of E 217βG by MRP7 in membrane vesicles transport assays. However, compounds that are able to reverse MRP7-mediated cellular resistance have not been identified. In this study, we examined the effects of cepharanthine (6′,12′-dimethoxy-2,2′-dimethyl-6,7-[methylenebis(oxy)]oxyacanthan), an herbal extract isolated from Stephania cepharantha Hayata, to reverse paclitaxel resistance in MRP7-transfected HEK293 cells. Cepharanthine, at 2 μM, completely reversed paclitaxel resistance in MRP7-transfected cells. In contrast, the effect of cepharanthine on the parental transfected cells was significantly less than that on the MRP7-transfected cells. In addition, cepharanthine significantly increased the accumulation of paclitaxel in MRP7-transfected cells almost to the level of control cells in the absence of cepharanthine. The efflux of paclitaxel from MRP7-transfected cells was also significantly inhibited by cepharanthine. The ability of cepharanthine to inhibit MRP7 was analyzed in membrane vesicle assays using E 217βG, an established substrate of MRP7, as a probe. E 217βG transport was competitively inhibited by cepharanthine with a K i value of 4.86 μM. These findings indicate that cepharanthine reverses MRP7-mediated resistance to paclitaxel in a competitive manner.