Reversal of P-glycoprotein-mediated multidrug resistance by Alisol B 23-acetate

被引:72
作者
Wang, C [1 ]
Zhang, JX [1 ]
Shen, XL [1 ]
Wan, CK [1 ]
Tse, AKW [1 ]
Fong, WF [1 ]
机构
[1] City Univ Hong Kong, Dept Biol & Chem, Bioact Prod Res Grp, Kowloon, Hong Kong, Peoples R China
关键词
Alisol B 23-acetate; multidrug resistance; P-glycoprotein; chemosensitizer; triterpene;
D O I
10.1016/j.bcp.2004.05.021
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Herbal drugs were screened for their activity in reversing multidrug resistance (MDR) in P-glycoprotein (P-gp) over-expressing cancer cells. Through bio-assay guided fractionation an active compound was isolated from Rhizoma Alismatis, the underground part of Alisma orientale and the chemical structure of the isolate compound was confirmed by HPLC, LC-MS and NMR as Alisol B 23-acetate (ABA). ABA restored the sensitivity of MDR cell lines HepG2-DR and K562-DR to anti-tumor agents that have different modes of action but are all P-gp substrates. It restored the activity of vinblastine, a P-gp substrate, in causing G(2)/M arrest in MDR cells. In a dose-dependent manner, ABA increased doxorubicin accumulation and slowed down the efflux of rhodamin-123 from MDR cells. ABA inhibited the photoaffinity labeling of P-gp by [I-125]iodoarylazidoprazosin and stimulated the ATPase activity of P-gp in a concentration-dependent manner, suggesting that it could be a transporter substrate for P-gp. In addition, ABA was also a partial non-competitive inhibitor of P-gp when verapamil was used as a substrate. Our results suggest that ABA may be a potential MDR reversal agent and could serve as a lead compound in the development of novel drugs. (C) 2004 Elsevier Inc. All rights reserved.
引用
收藏
页码:843 / 855
页数:13
相关论文
共 30 条
[1]   Inhibition of P-glycoprotein expression and reversal of drug resistance of human hepatoma HepG2 cells by multidrug resistance gene (mdr1) antisense RNA [J].
Chan, JYW ;
Chu, ACY ;
Fung, KP .
LIFE SCIENCES, 2000, 67 (17) :2117-2124
[2]   Effect of alisol B acetate, a plant triterpene, on apoptosis in vascular smooth muscle cells and lymphocytes [J].
Chen, HW ;
Hsu, MJ ;
Chien, CT ;
Huang, HC .
EUROPEAN JOURNAL OF PHARMACOLOGY, 2001, 419 (2-3) :127-138
[3]   ANALYSIS OF COMBINED DRUG EFFECTS - A NEW LOOK AT A VERY OLD PROBLEM [J].
CHOU, TC ;
TALALAY, P .
TRENDS IN PHARMACOLOGICAL SCIENCES, 1983, 4 (11) :450-454
[4]   QUANTITATIVE-ANALYSIS OF DOSE-EFFECT RELATIONSHIPS - THE COMBINED EFFECTS OF MULTIPLE-DRUGS OR ENZYME-INHIBITORS [J].
CHOU, TC ;
TALALAY, P .
ADVANCES IN ENZYME REGULATION, 1984, 22 :27-55
[5]  
CORNWELL MM, 1986, J BIOL CHEM, V261, P7921
[6]   Interaction of combinations of drugs, chemosensitisers, and peptides with the P-glycoprotein multidrug transporter [J].
DiDiodato, G ;
Sharom, FJ .
BIOCHEMICAL PHARMACOLOGY, 1997, 53 (12) :1789-1797
[7]  
Fan MY, 2000, CANCER RES, V60, P6403
[8]  
FORD JM, 1990, PHARMACOL REV, V42, P155
[9]   P-glycoprotein - A mediator of multidrug resistance in tumour cells [J].
Germann, UA .
EUROPEAN JOURNAL OF CANCER, 1996, 32A (06) :927-944
[10]   Effects of modulators of multidrug resistance on the expression of the MDR1 gene in human KB cells in culture [J].
Hu, YP ;
Pourquier, P ;
Doignon, F ;
Crouzet, M ;
Robert, J .
ANTI-CANCER DRUGS, 1996, 7 (07) :738-744