紫杉醇
转染
流出
药理学
多重耐药
ATP结合盒运输机
体外
化学
运输机
生物
生物化学
化疗
基因
遗传学
抗生素
作者
Ying Zhou,Elizabeth Hopper-Borge,Tong Shen,Xiaocong Huang,Zhi Shi,Yehong Kuang,Tatsuhiko Furukawa,Shin-ichi Akiyama,Xingxiang Peng,Charles R. Ashby,Xiang Chen,Gary D. Kruh,Zhe‐Sheng Chen
标识
DOI:10.1016/j.bcp.2008.12.005
摘要
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 E217βG 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 E217βG, an established substrate of MRP7, as a probe. E217βG transport was competitively inhibited by cepharanthine with a Ki value of 4.86 μM. These findings indicate that cepharanthine reverses MRP7-mediated resistance to paclitaxel in a competitive manner.
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