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Nutrition and Disease

Oral Administration of 3,3'-Diindolylmethane Inhibits Lung Metastasis of 4T1 Murine Mammary Carcinoma Cells in BALB/c Mice^1,2,3

⁴ Department of Food Science and Nutrition Hallym University, Chuncheon, 200-702, Korea ⁵ Center for Efficacy Assessment and Development of Functional Foods and Drugs, Hallym University, Chuncheon, 200-702, Korea ⁶ Department of Food Science and Biotechnology, Kangwon National University, Chuncheon, 200-701, Korea ⁷ Korea Food Research Institute, Songnam, 463-746, Korea

3,3'-diindolylmethane (DIM) is the major in vivo product of the acid-catalyzed oligomerization of indole-3-carbinol present in cruciferous vegetables, and it has been shown to exhibit anticancer properties. In this study, we assessed the effects of DIM on the metastasis of 4T1 mouse mammary carcinoma cells. In vitro culture studies showed that DIM dose-dependently inhibited the migration, invasion, and adhesion of 4T1 cells at concentrations of 0–10 µmol/L without attendant changes in cell viability. In an in vivo lung metastasis model, 4T1 cells (2 x 10⁵ cells/mouse) were injected into the tail veins of syngeneic female BALB/c mice. Beginning on the second day, the mice were subjected to gavage with 0–10 mg DIM/(kg body weight · d) for 13 d. Oral DIM administration resulted in a marked reduction in the number of pulmonary tumor nodules. DIM treatment significantly reduced the levels of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, and vascular cell adhesion molecule (VCAM)-1 and increased TIMP-2 levels in the sera and lungs of mice injected with 4T1 cells. Additionally, DIM treatment reduced the serum concentrations of interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF). We have demonstrated that DIM profoundly inhibits the lung metastasis of 4T1 cells, which was accompanied by reduced levels of MMP, adhesion molecules, and proinflammatory cytokines. These results indicate that DIM has potential as an antimetastatic agent for the treatment of breast cancer.

^* To whom correspondence should be addressed. E-mail: jyoon{at}hallym.ac.kr.

Manuscript received 19 June 2009. Initial review completed 3 August 2009. Revision accepted 16 October 2009.