Carcinogenesis Advance Access published online on October 4, 2007
Carcinogenesis, doi:10.1093/carcin/bgm223
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Decreased 7,12-dimethylbenz[a]anthracene-induced carcinogenesis coincides with the induction of anti-tumor immunities in adult female B6C3F1 mice pretreated with genistein1
* Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298-0613
2 To whom correspondence should be addressed: Tai L. Guo, Ph.D, Department of Pharmacology and Toxicology, Virginia Commonwealth University, PO Box 980613, Richmond, VA 23298-0613. Tel: (804) 828-6732, Fax: (804) 828-5604, E-mail: tlguo{at}vcu.edu.
The objective of this study was to determine if genistein modulation of the immune responses might contribute to the increased host resistances to tumors. A time course study was performed in adult female B6C3F1 mice that had been exposed to genistein for 1-4 weeks at the dose level of 20 mg/kg by gavage. A significant increase in ex vivo cytotoxic T lymphocyte (CTL) activity was observed in the periods of 2 weeks and 4 weeks. Moreover, increased activities of CTLs were associated with a decrease in the percentage of CD4+CD25+ T cells, and an increase in the production of IFN-
and activation of STAT1 and STAT4. Additionally, exposure of mice to genistein increased the activities of in vivo CTLs. An increased activity of natural killer cells was also observed. Further study in the B16F10 tumor model suggested that genistein-mediated enhancement in host resistance to B16F10 tumor was partially related to its potentiating effect on NK cells. Finally, DMBA-induced tumor model was employed to determine the chemopreventive effect of oral genistein treatment. Mice pretreated with genistein for 2 weeks by gavage, the time when an enhanced CTL activity had been produced, had a decreased susceptibility toward DMBA-mediated carcinogenesis while treatment with genistein after tumor induction conferred no protection. In conclusion, pretreatment with genistein by gavage could enhance host resistances to the B16F10 tumor and DMBA-induced carcinogenesis, suggesting that genistein modulation of immune response was, at least partially, responsible for the anti-tumor effect of this compound.
Key Words: genistein • cytotoxic T cell activity • STATs • CD4+CD25+ T cells • natural killer cell activity • DMBA tumor model and B16F10 tumor model
1 This study was supported in part from ES012286 and NIEHS contract NO1-ES-05454. The authors would like to thank KL White and DL Musgrove for their discussion and R. D. Brown for her technical help, and Connie Weis (NCTR, U.S. FDA, Jefferson, AR 72079) for providing genistein feed in the conducted studies
Received June 11, 2007; revised September 19, 2007; accepted September 22, 2007.