DIM for Prostate Health

Prostate. 2004 Oct 1;61(2):153-60.

Therapeutic activity of 3,3'-diindolylmethane on prostate cancer in an in vivo model.

Nachshon-Kedmi M, Fares FA, Yannai S.

Faculty of Food Engineering and Biotechnology, Technion-Israel Institute of Technology, Haifa, Israel.

BACKGROUND: Prostate cancer (PC) is the second leading cancer-related death in men in Western countries. Hence, efficient anti-carcinogenic and therapeutic compounds against PC are badly needed. We have previously shown that 3,3'-diindolylmethane (DIM) has a suppressive effect on the growth of human breast and PC cell lines. The objective of this study was examination of the potential therapeutic effects of DIM in an in vivo model. METHODS: TRAMP-C2, a mouse PC cell line, was injected into the flank of male C57BL/6 mice. When tumors appeared, mice were injected intraperitoneally with either corn oil (vehicle) or DIM (2.5, 5, or 10 mg per kg body weight) 3-times a week, for 3 weeks, and tumor volumes were measured bi-weekly with calibermeters. Later, the tumors were removed, their final weights and volumes were measured, and tumor sections were tested for histological studies. RESULTS: DIM had a significant inhibitory effect, caused by diminished tumor growth. Histological examination of tumors from treated groups revealed apoptosis and decreased cell proliferation, compared with the controls. DIM didn't affect body weights or kidney and liver functioning. CONCLUSIONS: The inhibitory action of DIM on tumor growth was demonstrated in vivo. Hence, this compound at the concentrations tested may offer an effective and non toxic therapeutic means against tumor growth in rodents, and may serve as a potential natural anti-carconigenic compound in humans. Copyright 2004 Wiley-Liss, Inc

Cancer. 2003 Dec 1;98(11):2511-20

Indole-3-carbinol induces a G1 cell cycle arrest and inhibits prostate-specific antigen production in human LNCaP prostate carcinoma cells.

Zhang J, Hsu B A JC, Kinseth B A MA, Bjeldanes LF, Firestone GL.

Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720-3200, USA.

BACKGROUND: Indole-3-carbinol (I3C), a naturally occurring component of Brassica vegetables, such as cabbage, broccoli, and Brussels sprouts, is a promising anticancer agent for certain reproductive tumor cells. The objective of the current study was to characterize the cell cycle effects of I3C in human prostate carcinoma cells. METHODS: The incorporation of [(3)H]thymidine and flow cytometry of propidium iodide-stained nuclei were used to monitor I3C-regulated changes in prostate carcinoma cell proliferation and cell cycle progression. Western blotting was used to document expression changes in cell cycle components and prostate-specific antigen (PSA) levels. The enzymatic activities of cyclin-dependent kinases (CDK) were tested by in vitro protein kinase assays using the retinoblastoma protein as a substrate. RESULTS: I3C suppressed the growth of LNCaP prostate carcinoma cells in a dose-dependent manner by inducing a G1 block in cell cycle progression. I3C selectively inhibited the expression of CDK6 protein and transcripts and strongly stimulated the production of the p16 CDK inhibitor. In vitro protein kinase assays revealed the striking inhibition by I3C of immunoprecipitated CDK2 enzymatic activity and the relatively minor down-regulation of CDK4 enzymatic activity. In LNCaP prostate carcinoma cells, I3C treatment inhibited production of PSA, whereas combinations of I3C and the androgen antagonist flutamide more effectively inhibited DNA synthesis and PSA levels compared with either agent alone. CONCLUSIONS: The results of the current study demonstrated that I3C has a potent antiproliferative effect in LNCaP and other human prostate carcinoma cells. These findings implicate this dietary indole as a potential chemotherapeutic agent for controlling the growth of human prostate carcinoma cells. Copyright 2003 American Cancer Society.

Br J Cancer. 2004 Oct 4;91(7):1358-63.

Induction of apoptosis in human prostate cancer cell line, PC3, by 3,3'-diindolylmethane through the mitochondrial pathway.

Nachshon-Kedmi M, Yannai S, Fares FA.

Faculty of Food Engineering and Biotechnology, Technion-Israel Institute of Technology, Haifa 32000, Israel.

Prostate cancer is the most common malignancy and the second leading cause of male death in Western countries. Prostate cancer mortality results from metastases to the bones and lymph nodes and progression from androgen-dependent to androgen-independent disease. Although androgen ablation was found to be effective in treating androgen-dependent prostate cancer, no effective life-prolonging therapy is available for androgen-independent cancer. Epidemiological studies have shown a strong correlation between consumption of cruciferous vegetables and a lower risk of prostate cancer. These vegetables contain glucosinolates, which during metabolism give rise to several breakdown products, mainly indole-3-carbinol (I3C), which may be condensed to polymeric products, especially 3,3'-diindolylmethane (DIM). It was previously shown that these indole derivatives have significant inhibitory effects in several human cancer cell lines, which are exerted through induction of apoptosis. We have previously reported that I3C and DIM induce apoptosis in prostate cancer cell lines through p53-, bax-, bcl-2- and fasL-independent pathways. The objective of this study was examination of the apoptotic pathways that may be involved in the effect of DIM in the androgen-independent prostate cancer cell line, PC3, in vitro. Our results suggest that DIM induces apoptosis in PC3 cells, through the mitochondrial pathway, which involves the translocation of cytochrome c from the mitochondria to the cytosol and the activation of initiator caspase, 9, and effector caspases, 3 and 6, leading to poly ADP-ribose polymerase (PARP) cleavage and induction of apoptosis. Our findings may lead to the development of new therapeutic strategies for the treatment of androgen-independent prostate cancer.