Acerinol, a cyclolanstane triterpenoid from Cimicifuga acerina, reverses ABCB1-mediated multidrug resistance in HepG2/ADM and MCF-7/ADR cells.
Persistent cancer chemotherapy can lead to multidrug resistance which is one of the most common reasons for failure of chemotherapy. The ABCB1 transporter is a member of the ATP-binding cassette superfamily and it is frequently over-expressed in multidrug resistant cancer cells. Active ingredients derived from traditional Chinese medicinal herbs have been reported to reverse multidrug resistance mediated by ATP-binding cassette transporters. In this study, acerinol, isolated from Cimicifuga acerina, was tested for its potential to modulate the ABCB1 transporter. Our results demonstrated that acerinol could increase the chemosensitivity of ABCB1-overexpressing HepG2/ADM and MCF-7/ADR cells to chemotherapeutic drugs, doxorubicin, vincristine and paclitaxel. Furthermore, it could also increase the retention of ABCB1 substrates doxorubicin and rhodamine 123 in HepG2/ADM and MCF-7/ADR cells. A mechanistic study showed that acerinol significantly stimulated the activity of ABCB1 ATPase without affecting the expression of ABCB1 on neither mRNA nor protein level. Acerinol was also found to reverse the resistance of MCF-7/ADR cells to vincristine, dependent partly on ABCB1. In addition, acerinol׳s action was reversible, suggesting that acerinol may act as a competitive inhibitor of ABCB1 by competing with other drug substrates like doxorubicin. Indeed, docking analysis indicated that acerinol would most likely bind to the sites on ABCB1 that partly overlapped with that of verapamil. In conclusion, the present study is the first to show that acerinol from C. acerina significantly enhances the cytotoxicity of chemotherapeutic drugs by modulating the function of ABCB1. It is hopeful to develop acerinol as a new multidrug resistance reversal agent.
College of Pharmacy, Jinan University, Guangzhou 510632, PR China.
Dao-Lu
DL
Liu
College of Pharmacy, Jinan University, Guangzhou 510632, PR China.
Ying-Jie
YJ
Li
College of Pharmacy, Jinan University, Guangzhou 510632, PR China.
Nan
N
Yao
College of Pharmacy, Jinan University, Guangzhou 510632, PR China.
Jun
J
Xu
College of Pharmacy and Health Sciences, St. John׳s University, Queens, NY, USA.
Zhe-Sheng
ZS
Chen
School of Life Sciences, The Chinese University of Hong Kong, Hong Kong.
Anita
A
Yiu
School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510006, PR China.
Cui-Xian
CX
Zhang
College of Pharmacy, Jinan University, Guangzhou 510632, PR China. Electronic address: chywc@yahoo.com.cn.
Wen-Cai
WC
Ye
College of Pharmacy, Jinan University, Guangzhou 510632, PR China. Electronic address: dmzhang701@foxmail.com.
Dong-Mei
DM
Zhang
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000235:genetics; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D031885:Cimicifuga / Q000737:chemistry*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013379:Substrate Specificity; D014315:Triterpenes / Q000302:isolation & purification / Q000494:pharmacology*
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D014315:Triterpenes; C023726:acerinol; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
ABCB1; Acerinol; HepG2/ADM; MCF-7/ADR; Multidrug resistance