Growth inhibition, cell-cycle dysregulation, and induction of apoptosis by green tea constituent (-)-epigallocatechin-3-gallate in androgen-sensitive and androgen-insensitive human prostate carcinoma cells

被引:244
作者
Gupta, S
Ahmad, N
Nieminen, AL
Mukhtar, H
机构
[1] Case Western Reserve Univ, Dept Dermatol, Cleveland, OH 44106 USA
[2] Case Western Reserve Univ, Dept Anat, Cleveland, OH 44106 USA
关键词
epigallocatechin-3-gallate; apoptosis; cell cycle arrest; chemoprevention; prostate cancer;
D O I
10.1006/taap.1999.8885
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Prostate cancer (PCA) is the most prevalent cancer diagnosed and the second leading cause of cancer-related deaths among men in the United States. Descriptive epidemiological data suggest that androgens and environmental exposures play a key role in prostatic carcinogenesis. Since androgen action is intimately associated with proliferation and differentiation, at the time of clinical diagnosis in humans most PCA represent themselves as a mixture of androgen-sensitive and androgen-insensitive cells. Androgen-sensitive cells undergo rapid apoptosis upon androgen withdrawal. On the other hand, the androgen-insensitive cells do not undergo apoptosis upon androgen blocking, but maintain the molecular machinery of apoptosis. Thus, agents capable of inhibiting growth and/or inducing apoptosis in both androgen-sensitive and androgen-insensitive cells will be useful for the management of PCA. In the present study, we show that (-)-epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent present in green tea, imparts antiproliferative effects against both androgen-sensitive and androgen-insensitive human PCA cells, and this effect is mediated by deregulation in cell cycle and induction of apoptosis. EGCG treatment,vas found to result in a dose-dependent inhibition of cell growth in both androgen-insensitive DU145 and androgen-sensitive LNCaP cells. In both the cell types, EGCG treatment also resulted in a dose-dependent G(0)/G(1)-phase arrest of the cell cycle as observed by DNA cell-cycle analysis. As evident by DNA ladder assay, confocal microscopy, and flow cytometry, the treatment of both DU145 and LNCaP cells with EGCG resulted in a dose-dependent apoptosis. Western blot analysis revealed that EGCG treatment resulted in (i) a dose-dependent increase of p53 in LNCaP cells (carrying wild-type p53), but not in DU145 cells (carrying mutant p53), and (ii) induction of cyclin kinase inhibitor WAF1/p21 in both cell types. These results suggest that EGCG negatively modulates PCA cell growth, by affecting mitogenesis as web as inducing apoptosis, in cell-type-specific manner which may be mediated by WAF1/p21-caused G(0)/G(1)-phase cell-cycle arrest, irrespective of the androgen association or p53 status of the cells. (C) 2000 Academic Press.
引用
收藏
页码:82 / 90
页数:9
相关论文
共 70 条
[1]   The p53 network [J].
Agarwal, ML ;
Taylor, WR ;
Chernov, MV ;
Chernova, OB ;
Stark, GR .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (01) :1-4
[2]  
Ahmad N, 1999, NUTR REV, V57, P78, DOI 10.1111/j.1753-4887.1999.tb06927.x
[3]   Green tea constituent epigallocatechin-3-gallate and induction of apoptosis and cell cycle arrest in human carcinoma cells [J].
Ahmad, N ;
Feyes, DK ;
Nieminen, AL ;
Agarwal, R ;
Mukhtar, H .
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1997, 89 (24) :1881-1886
[4]   SITE-SPECIFIC DNA CLEAVAGE BY MAMMALIAN DNA TOPOISOMERASE-II INDUCED BY NOVEL FLAVONE AND CATECHIN DERIVATIVES [J].
AUSTIN, CA ;
PATEL, S ;
ONO, K ;
NAKANE, H ;
FISHER, LM .
BIOCHEMICAL JOURNAL, 1992, 282 :883-889
[5]   (-)-epigallocatechin-3-gallate inhibition of ultraviolet B induced AP-1 activity [J].
Barthelman, M ;
Bair, WB ;
Stickland, KK ;
Chen, WX ;
Timmermann, N ;
Valcic, S ;
Dong, ZG ;
Bowden, GT .
CARCINOGENESIS, 1998, 19 (12) :2201-2204
[6]  
Blot WJ, 1996, EUR J CANCER PREV, V5, P425
[7]   Green tea and cancer in humans: A review of the literature [J].
Bushman, JL .
NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL, 1998, 31 (03) :151-159
[8]   Angiogenesis inhibited by drinking tea [J].
Cao, YH ;
Cao, RH .
NATURE, 1999, 398 (6726) :381-381
[9]   Green tea epigallocatechin gallate shows a pronounced growth inhibitory effect on cancerous cells but not on their normal counterparts [J].
Chen, ZP ;
Schell, JB ;
Ho, CT ;
Chen, KY .
CANCER LETTERS, 1998, 129 (02) :173-179
[10]  
Conney AH, 1997, P SOC EXP BIOL MED, V216, P234, DOI 10.3181/00379727-216-44173