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

Abstract

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 microM 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, p27(Kip1), 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.

• Authors: Xiaofei Chang, Janet C Tou, Chibo Hong, Hyeon-A Kim, Jacques E Riby, Gary L Firestone, Leonard F Bjeldanes
• Journal: Carcinogenesis (Carcinogenesis) Vol. 26 Issue 4 Pg. 771-8 (Apr 2005) ISSN: 0143-3334 [Print] England
• PMID: 15661811 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Angiogenesis Inhibitors
• Anticarcinogenic Agents
• Indoles
• 3,3'-diindolylmethane

Topics

• Angiogenesis Inhibitors (therapeutic use)
• Animals
• Anticarcinogenic Agents (therapeutic use)
• Breast Neoplasms (blood supply, drug therapy, metabolism)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Endothelial Cells (drug effects, metabolism)
• Female
• G1 Phase (drug effects)
• Humans
• Indoles (therapeutic use)
• Mice
• Mice, Inbred C57BL
• Mice, Nude
• Neoplasm Invasiveness (pathology)
• Neovascularization, Pathologic (prevention & control)
• Tumor Cells, Cultured (transplantation)
• Umbilical Veins
• Xenograft Model Antitumor Assays