Abstract

Indole-3-carbinol (I3C) is a naturally occurring component of cruciferous vegetables and has promise as a cancer preventive agent, most notably against breast cancer. The hypothesis to be tested in this proposal is that the antiestrogenic growth inhibitory activity of I3C results from its conversion to products which bind to the aryl hydroxylase receptor (AhR) leading to increased estrogen metabolism and/or decreased cell sensitivity to estrogen.
Three specific aims are proposed to investigate this hypothesis: (1) identify I3C products that are responsible for I3C's growth inhibitory effects in estrogen-responsive tumor cells; (2) determine AhR-related activities of growth inhibitors; and (3) characterize antiestrogenic effects of growth inhibitors and determine whether the AhR is required for these effects. In order to carry out this work, the investigators propose to fractionate reaction mixtures resulting from acid or neutral treatment of I3C and examine the purified conversion products for growth inhibitory activity using estrogen responsive MCF-7 cells. Growth inhibitory products will then be further analyzed for their effects on AhR and estrogen receptor mediated gene expression, receptor affinity, receptor binding to response elements, and induction of AhR and ER-responsive reporter constructs in transfected tumor cells. To determine if the growth inhibitory effects of the I3C conversion products depend on AhR, AhR antisense blocking experiments will be conducted.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA069056-04
Application #
2895412
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Kim, Young Shin
Project Start
1996-07-01
Project End
2000-06-30
Budget Start
1999-05-01
Budget End
2000-06-30
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
University of California Berkeley
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
094878337
City
Berkeley
State
CA
Country
United States
Zip Code
94704

  Publications

Nicastro, Holly L; Firestone, Gary L; Bjeldanes, Leonard F (2013) 3,3'-diindolylmethane rapidly and selectively inhibits hepatocyte growth factor/c-Met signaling in breast cancer cells. J Nutr Biochem 24:1882-8
Vivar, Omar I; Saunier, Elise F; Leitman, Dale C et al. (2010) Selective activation of estrogen receptor-beta target genes by 3,3'-diindolylmethane. Endocrinology 151:1662-7
Vivar, Omar I; Lin, Chia-Lei; Firestone, Gary L et al. (2009) 3,3'-Diindolylmethane induces a G(1) arrest in human prostate cancer cells irrespective of androgen receptor and p53 status. Biochem Pharmacol 78:469-76
Riby, Jacques E; Firestone, Gary L; Bjeldanes, Leonard F (2008) 3,3'-diindolylmethane reduces levels of HIF-1alpha and HIF-1 activity in hypoxic cultured human cancer cells. Biochem Pharmacol 75:1858-67
Xue, Ling; Pestka, James J; Li, Maoxiang et al. (2008) 3,3'-Diindolylmethane stimulates murine immune function in vitro and in vivo. J Nutr Biochem 19:336-44
Gong, Yixuan; Sohn, Heesook; Xue, Ling et al. (2006) 3,3'-Diindolylmethane is a novel mitochondrial H(+)-ATP synthase inhibitor that can induce p21(Cip1/Waf1) expression by induction of oxidative stress in human breast cancer cells. Cancer Res 66:4880-7
Riby, Jacques E; Xue, Ling; Chatterji, Urmi et al. (2006) Activation and potentiation of interferon-gamma signaling by 3,3'-diindolylmethane in MCF-7 breast cancer cells. Mol Pharmacol 69:430-9
Gong, Yixuan; Firestone, Gary L; Bjeldanes, Leonard F (2006) 3,3'-diindolylmethane is a novel topoisomerase IIalpha catalytic inhibitor that induces S-phase retardation and mitotic delay in human hepatoma HepG2 cells. Mol Pharmacol 69:1320-7
Chang, Xiaofei; Firestone, Gary L; Bjeldanes, Leonard F (2006) Inhibition of growth factor-induced Ras signaling in vascular endothelial cells and angiogenesis by 3,3'-diindolylmethane. Carcinogenesis 27:541-50
Staub, Richard E; Onisko, Bruce; Bjeldanes, Leonard F (2006) Fate of 3,3'-diindolylmethane in cultured MCF-7 human breast cancer cells. Chem Res Toxicol 19:436-42

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