Carcinogenesis Advance Access published online on January 20, 2005
Carcinogenesis, doi:10.1093/carcin/bgi018
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1 Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720, USA
* To whom correspondence should be addressed. Studies have linked the consumption of broccoli and other cruciferous vegetables to reduced risk of breast cancer. The phytochemical indole-3-carbinol (I3C), present in cruciferous vegetables, and its major acid-catalyzed reaction product 3,3'-diindolylmethane (DIM) have bioactivities relevant to the inhibition of carcinogenesis. In this study, the effect of DIM on angiogenesis and tumorigenesis in a rodent model were investigated. We found that DIM produced a concentration-dependent decrease in proliferation, migration, invasion, and capillary tube formation of cultured human umbilical vein endothelial cells (HUVECs). Consistent with its antiproliferative effect, which was significant at only 5 µM DIM, this indole caused a G1 cell cycle arrest in actively proliferating HUVECs. Furthermore, DIM down-regulated expression of cyclin-dependent kinase 2 and 6 (CDK2, CDK6), and upregulated expression of CDK inhibitor, p27Kip1, in HUVECs. We observed further in a complementary in vivo Matrigel plug angiogenesis assay that, compared with vehicle control, neovascularization was inhibited up to 76% following administration of 5 mg/kg DIM to female C57BL/6 mice. Finally, this dose of DIM also inhibited the growth of human MCF-7 cell tumor xenografts by up to 64% in female athymic (nu/nu) mice, compared to the vehicle control. This is the first study to show that DIM can strongly inhibit human breast tumor development in a xenograft model and to provide evidence for the antiangiogenic properties of this dietary indole.
Received August 17, 2004
Revised December 6, 2004
Accepted January 8, 2005
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
3,3'-diindolylmethane inhibits angiogenesis and the growth of transplantable human breast carcinoma in athymic mice
2 Department of Molecular Cell Biology, University of California, Berkeley, California 94720, USA
Leonard F. Bjeldanes, E-mail: lfb{at}nature.berkeley.edu
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