Journal Article

3,3′-Diindolylmethane inhibits angiogenesis and the growth of transplantable human breast carcinoma in athymic mice

Xiaofei Chang, Janet C. Tou, Chibo Hong, Hyeon-A. Kim, Jacques E. Riby, Gary L. Firestone and Leonard F. Bjeldanes

in Carcinogenesis

Volume 26, issue 4, pages 771-778
Published in print April 2005 | ISSN: 0143-3334
Published online April 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi018
3,3′-Diindolylmethane inhibits angiogenesis and the growth of transplantable human breast carcinoma in athymic mice

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Studies have linked the consumption of broccoli and other cruciferous vegetables to a 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 was 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 downregulated the expression of cyclin-dependent kinases 2 and 6 (CDK2, CDK6), and upregulated the 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 the 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 with the vehicle control. This is the first study to show that DIM can strongly inhibit the development of human breast tumor in a xenograft model and to provide evidence for the antiangiogenic properties of this dietary indole.

Keywords: aFGF, acidic fibroblast growth factor; CDK, cyclin-dependent kinase; CKI, cyclin-dependent kinase inhibitor; DIM, 3,3′-diindolylmethane; DMSO, dimethyl sulfoxide; HUVECs, human umbilical vein endothelial cells; I3C, indole-3-carbinol; s.c., subcutaneous

Journal Article.  6586 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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