Many cancers could be prevented by diet. The connection between plant-derived dietary ingredients and the prevention of major cancers, especially the hormone-dependent cancers, is just beginning to be appreciated. Ongoing research concerns the phytochemical indole-3- carbinol (I3C), from cruciferous vegetables. I3C uniquely causes detoxification of marry carcinogens and """"""""favorable"""""""" metabolism of estrogen. I3C and its acid condensation products are proving useful in preventing many cancers including those initiated by papillomavirus, viruses which increase susceptibility of cells to malignant transformation, as in the case of cervical cancer. 13C is anti-estrogenic and prevents estradiol-promoted cervical cancer in the HPV-transgenic mouse. Current studies show that I3C induces apoptosis and decreases proliferation of cervical cells, both processess incompatible with cancer. We find I3C decreases Bcl-2 and increases BRCA-1, PTEN and TNFalpha; others show I3C affects CDK6. This proposal is to understand the mechanisms underlying the anti-cancer activities of I3C. It is probable that regulation of tumor formation and growth by I3C has estrogen-dependent and estrogen-independent components. Two different but related approaches include: in vivo experiments using normal mice and mice expressing BPV16 transgenes, and in vitro experiments to test specific mechanistic hypothesis. In vivo, the specific aims are to determine whether BC and its acid condensation product diindolymethane (DIM) both prevent and are useful in the treatment of cervical cancer , and whether DC/DIM decreases cell proliferation and increases apoptosis in developing tumors. In vitro, effects of I3C/D1M on cervical cells will be evaluated in relation to regulation of Bcl-2, BRCA-1, TNFalpha, P'TEN, CDK2 and CDK6, either by direct action at their promoters through the Ah receptor, or indirectly, by post-translational modification induced by estrogen metabolites such as 2-methoxy-estradiol. We will use gene chip technology to look for induction or repression of other genes involved in apoptosis and cell cycle progression.
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