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

• Published in: Carcinogenesis (New York) 2005-04, Vol.26 (4), p.771-778
• Main Authors: Chang, Xiaofei, Tou, Janet C., Hong, Chibo, Kim, Hyeon-A., Riby, Jacques E., Firestone, Gary L., Bjeldanes, Leonard F.
• Format: Article
• Language: English
• Subjects: 3′-diindolylmethane; acidic fibroblast growth factor; aFGF; Angiogenesis Inhibitors - therapeutic use; Animals; Anticarcinogenic Agents - therapeutic use; Biological and medical sciences; Breast Neoplasms - blood supply; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Carcinogenesis, carcinogens and anticarcinogens; CDK; Cell Movement - drug effects; Cell Proliferation - drug effects; CKI; cyclin-dependent kinase; cyclin-dependent kinase inhibitor; DIM; dimethyl sulfoxide; DMSO; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Female; G1 Phase - drug effects; human umbilical vein endothelial cells; Humans; HUVECs; I3C; indole-3-carbinol; Indoles - therapeutic use; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Nude; Neoplasm Invasiveness - pathology; Neovascularization, Pathologic - prevention & control; s.c; subcutaneous; Tumor Cells, Cultured - transplantation; Tumors; Umbilical Veins; Xenograft Model Antitumor Assays
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgi018

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.