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

作者：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., Jr.; Chen, Xiang; Kruh, Gary D.; Chen, Zhe-Sheng^*

来源：Biochemical Pharmacology, 2009, 77(6): 993-1001.

DOI：10.1016/j.bcp.2008.12.005

• MRP7
• MDR
• Cepharanthine
• Paclitaxel
• E(2)17 beta G transport

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(2)17 beta G 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 mu M, 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(2)17 beta G, an established substrate of MRP7, as a probe. E(2)17 beta G transport was competitively inhibited by cepharanthine with a K-i value of 4.86 mu M. These findings indicate that cepharanthine reverses MRP7-mediated resistance to paclitaxel in a competitive manner.

• 出版日期2009-3-15
• 单位中南大学