Cepharanthine is a potent reversal agent for MRP7(ABCC10)-mediated multidrug resistance.
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)17betaG 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 2microM, 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)17betaG, an established substrate of MRP7, as a probe. E(2)17betaG transport was competitively inhibited by cepharanthine with a K(i) value of 4.86microM. These findings indicate that cepharanthine reverses MRP7-mediated resistance to paclitaxel in a competitive manner.
Zhou
Ying
Y
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, NY, USA.
Hopper-Borge
Elizabeth
E
Shen
Tong
T
Huang
Xiao-Cong
XC
Shi
Zhi
Z
Kuang
Ye-Hong
YH
Furukawa
Tatsuhiko
T
Akiyama
Shin-Ichi
S
Peng
Xing-Xiang
XX
Ashby
Charles R
CR
Chen
Xiang
X
Kruh
Gary D
GD
Chen
Zhe-Sheng
ZS
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D044182:Benzylisoquinolines / Q000737:chemistry / Q000494:pharmacology*; D001693:Biological Transport, Active / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D017239:Paclitaxel / Q000378:metabolism / Q000494:pharmacology; D052117:Benzodioxoles
D000972:Antineoplastic Agents, Phytogenic; D044182:Benzylisoquinolines; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel; C421142:ABCC10 protein, human; C006947:cepharanthine; D052117:Benzodioxoles