Effects of genistein and structurally related phytoestrogens on cell cycle kinetics and apoptosis in MDA-MB-468 human breast cancer cells

被引:7
作者
Balabhadrapathruni, S
Thomas, TJ
Yurkow, EJ
Amenta, PS
Thomas, T
机构
[1] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Med, New Brunswick, NJ 08903 USA
[2] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Pathol & Lab Med, New Brunswick, NJ 08903 USA
[3] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Pathol & Lab Med, New Brunswick, NJ 08903 USA
[4] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Environm & Community Med, New Brunswick, NJ 08903 USA
[5] Canc Inst New Jersey, New Brunswick, NJ 08903 USA
[6] Environm & Occupat Hlth Sci Inst, New Brunswick, NJ 08903 USA
[7] Rutgers State Univ, Dept Pharmacol & Toxicol, Piscataway, NJ 08854 USA
[8] Rutgers State Univ, Nutr Sci Grad Program, New Brunswick, NJ 08901 USA
关键词
genistein; phytoestrogens; apoptosis; breast cancer;
D O I
暂无
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
We have studied the effects of phytoestrogens (genistein, quercetin, daidzein, biochanin A and kaempferol) on proliferation, cell cycle kinetics, and apoptosis of MDA-MB-468 breast cancer cells. Genistein and quercetin inhibited cell growth with IC50 values of 8.8 and 18.1 mu M, respectively, while the other phytoestrogens were less effective. Flow cytometric analysis showed G(2)/M cell cycle arrest with 25 mu M and higher concentrations of genistein. At 100 mu M, genistein, quercetin and kaempferol caused accumulation of 70, 60 and 35% of cells, respectively, in G2/M phase by 24 h. In contrast, biochanin A and daidzein were ineffective. APO-BRDU analysis revealed apoptosis with 10 mu M genistein (19.5%), reaching 86% at 100 mu M. Apoptosis by genistein was confirmed by Hoechst 33342 staining and fluorescence microscopy. With 100 mu M quercetin, 47% of the cells were apoptotic, while the other bioflavonoids had little effect. Genistein treatment resulted in a biphasic response on cyclin B1: 70% increase in cyclin B1 level at 25 mu M, and 50 and 70% decrease at 50 and 100 mu M, respectively. In contrast, the action of quercetin involved an increase in cyclin B1 level. Genistein had no effect on cdc2 level up to 50 mu M concentration; however, there was a decrease in the phosphorylated form of the protein at 100 mu M. Quercetin had no effect on cdc2 levels. Our results suggest that the action of genistein and quercetin involves G(2)/M arrest and apoptosis in MDA-MB-468 cells. Biochanin A and daidzein, although structurally related to genistein, did not share this mechanism. Thus, structurally related phytoestrogens have discrete target sites and mechanisms in their growth inhibitory action on breast cancer cells.
引用
收藏
页码:3 / 12
页数:10
相关论文
共 51 条
[1]   DIETARY PHYTOESTROGENS AND CANCER - INVITRO AND INVIVO STUDIES [J].
ADLERCREUTZ, H ;
MOUSAVI, Y ;
CLARK, J ;
HOCKERSTEDT, K ;
HAMALAINEN, E ;
WAHALA, K ;
MAKELA, T ;
HASE, T .
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, 1992, 41 (3-8) :331-337
[2]   URINARY-EXCRETION OF LIGNANS AND ISOFLAVONOID PHYTOESTROGENS IN JAPANESE MEN AND WOMEN CONSUMING A TRADITIONAL JAPANESE DIET [J].
ADLERCREUTZ, H ;
HONJO, H ;
HIGASHI, A ;
FOTSIS, T ;
HAMALAINEN, E ;
HASEGAWA, T ;
OKADA, H .
AMERICAN JOURNAL OF CLINICAL NUTRITION, 1991, 54 (06) :1093-1100
[3]   Morphological and biochemical characterization and analysis of apoptosis [J].
Allen, RT ;
Hunter, WJ ;
Agrawal, DK .
JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS, 1997, 37 (04) :215-228
[4]  
AVILA MA, 1994, CANCER RES, V54, P2424
[5]  
CastiglioneGertsch M, 1996, J CLIN ONCOL, V14, P1885
[6]  
Choi YH, 1998, INT J ONCOL, V13, P391
[7]   Genistein inactivates bcl-2, delays the G2/M phase of the cell cycle, and induces apoptosis of human breast adenocarcinoma MCF-7 cells [J].
Constantinou, AI ;
Kamath, N ;
Murley, JS .
EUROPEAN JOURNAL OF CANCER, 1998, 34 (12) :1927-1934
[8]   Genistein induces maturation of cultured human breast cancer cells and prevents tumor growth in nude mice [J].
Constantinou, AI ;
Krygier, AE ;
Mehta, RR .
AMERICAN JOURNAL OF CLINICAL NUTRITION, 1998, 68 (06) :1426S-1430S
[9]  
Ferry DR, 1996, CLIN CANCER RES, V2, P659
[10]   Genistein in the control of breast cancer cell growth: insights into the mechanism of action in vitro [J].
Fioravanti, L ;
Cappelletti, V ;
Miodini, P ;
Ronchi, E ;
Brivio, M ;
Di Fronzo, G .
CANCER LETTERS, 1998, 130 (1-2) :143-152