Modulation of P-glycoprotein function and reversal of multidrug resistance by (-)-epigallocatechin gallate in human cancer cells

被引:77
作者
Qian, F [1 ]
Wei, DZ [1 ]
Zhang, Q [1 ]
Yang, SL [1 ]
机构
[1] E China Univ Chem Technol, New World Inst Biotechnol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China
基金
中国国家自然科学基金;
关键词
(-)-epigallocatechin gallate; multidrug resistance; P-glycoprotein;
D O I
10.1016/j.biopha.2005.01.002
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Multidrug resistance (MDR) is a major obstacle in the chemotherapeutic treatment of many human cancers. In this study, the reversal of P-glycoprotein (P-gp) mediated multidrug resistance by (-)-epigallocatechin gallate (EGCG) and its molecular mechanism were investigated. A three-dimensional model of carboxyl-terminal nucleotide binding domain (NBD2) from P-gp was built by homology modeling. The structural model of the complex indicates that EGCG was tightly bound to the ATP-binding site of NBD2. EGCG modulated the function of P-gp and increased the intracellular accumulation of chemotherapeutic agent doxorubicin (DOX) in drug-resistant KB-A1 cells. When KB-A1 cells were exposed to 10 mu g/ml DOX combined with 10, 30, 50 mu M EGCG for 4 h, the intracellular concentrations of DOX were increased 1.5, 1.9, 2.3 times, respectively compared with DOX alone treatment. In vitro EGCG potentiated the cytotoxicity of DOX to drug-resistant KB-A1 cells. In KB-A1 cell xenograft model, EGCG could also enhance the efficacy of DOX and increased the DOX concentration in the resistant tumors. Thus, these results suggest that EGCG modulated the function of P-gp and reversed P-gp mediated multidrug resistance in human cancer cells. (c) 2005 Elsevier SAS. All rights reserved.
引用
收藏
页码:64 / 69
页数:6
相关论文
共 28 条
[1]   Biochemical, cellular, and pharmacological aspects of the multidrug transporter [J].
Ambudkar, SV ;
Dey, S ;
Hrycyna, CA ;
Ramachandra, M ;
Pastan, I ;
Gottesman, MM .
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, 1999, 39 :361-398
[2]   Modulation of P-glycoprotein expression and function by curcumin in multidrug-resistant human KB cells [J].
Anuchapreeda, S ;
Leechanachai, P ;
Smith, MM ;
Ambudkar, SV ;
Limtrakul, P .
BIOCHEMICAL PHARMACOLOGY, 2002, 64 (04) :573-582
[3]   Recent advances in the discovery of flavonoids and analogs with high-affinity binding to P-glycoprotein responsible for cancer cell multidrug resistance [J].
Boumendjel, A ;
Di Pietro, A ;
Dumontet, C ;
Barron, D .
MEDICINAL RESEARCH REVIEWS, 2002, 22 (05) :512-529
[4]   Structure of human uropepsin at 2.45 Å resolution [J].
Canduri, F ;
Teodoro, LGVL ;
Fadel, V ;
Lorenzi, CCB ;
Hial, V ;
Gomes, RAS ;
Neto, JR ;
de Azevedo, WF .
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 2001, 57 :1560-1570
[5]   Inhibition of drug transport by genistein in multidrug-resistant cells expressing P-glycoprotein [J].
Castro, AF ;
Altenberg, GA .
BIOCHEMICAL PHARMACOLOGY, 1997, 53 (01) :89-93
[6]   The antioxidant (-)-epigallocatechin-3-gallate inhibits rat hepatic stellate cell proliferation in vitro by blocking the tyrosine phosphorylation and reducing the gene expression of platelet-derived growth factor-β receptor [J].
Chen, AP ;
Zhang, L .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (26) :23381-23389
[7]   Molecular model for the binary complex of uropepsin and pepstatin [J].
de Azevedo, WF ;
Canduri, F ;
Fadel, V ;
Teodoro, LGVL ;
Hial, V ;
Gomes, RAS .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2001, 287 (01) :277-281
[8]   Inhibition of cyclin-dependent kinases by purine analogues - Crystal structure of human cdk2 complexed with roscovitine [J].
DeAzevedo, WF ;
Leclerc, S ;
Meijer, L ;
Havlicek, L ;
Strnad, M ;
Kim, SH .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1997, 243 (1-2) :518-526
[9]   Crystal structure of MalK, the ATPase subunit of the trehalose/maltose ABC transporter of the archaeon Thermococcus litoralis [J].
Diederichs, K ;
Diez, J ;
Greller, G ;
Müller, C ;
Breed, J ;
Schnell, C ;
Vonrhein, C ;
Boos, W ;
Welte, W .
EMBO JOURNAL, 2000, 19 (22) :5951-5961
[10]   Experimental reversal of P-glycoprotein-mediated multidrug resistance by pharmacological chemosensitisers [J].
Ford, JM .
EUROPEAN JOURNAL OF CANCER, 1996, 32A (06) :991-1001