Epidemiological studies have suggested that lower incidence of prostate cancer could be due to environmental factors, particularly dietary. Consumption of fruits and vegetables, which provides several classes of compounds, including indole-3- carbinol (I3C), may have a protective effect against the development of human prostate cancer. Despite the importance of I3C, knowledge on the molecular mechanism(s) of action of I3C in vitro and in vivo, and its anti-tumor activity against prostate cancer is lacking. Our preliminary results show that, for prostate cancer cells in culture, I3C and its in vivo dimeric product, Diindolylmethane (DIM) inhibits cell proliferation with a concomitant increase in apoptotic cell death by their pleitropic effects on several cell cycle and apoptosis related proteins. Most importantly, we observed inactivation of Akt and NF-kappaB signaling pathway by I3C/DIM in prostate cancer cells but not in non-tumorigenic prostate epithelial cells. Based on these preliminary results, we hypothesize that I3C and DIM (I3C/DIM) function as an inhibitor of Akt, leading to the inactivation of NF-kappaB, which in turn, causes cell growth inhibition and induction of apoptosis. We further hypothesize that I3C/DIM inhibits metastatic prostate tumor growth in experimental bone metastasis model in SCID mice, and that the animal tumors exposed to DIM will lead to alterations in the expression of specific genes, which will be the in vivo molecular targets of I3C/DIM in the processes of prostate cancer metastases. To test our hypotheses, we propose four specific aims.
In aim -1, we will determine whether treatment of non-tumorigenic and tumorigenic prostate epithelial cells with I3C/DIM inactivates the NF-kappaB pathway to the same or different degrees, and (b) investigate the mechanism(s) of NF-kappaB inactivation by measuring phosphorylation and ubiquitination of IkappaB and inhibition in the nuclear translocation of NF-kappaB using confocal microscopy, and correlate these results with apoptotic cell death.
In aim -2, we will investigate the mechanism(s) by which Akt inactivation leads to the down regulation of NF-kappaB by investigating cell signaling molecules that are important regulators of NF-kappaB such as MEKK1, MEK, NIK and IKK using gene transfection studies. These investigations will determine the cause and effect relationships between these signaling molecules and I3C/DIM induced apoptotic cell death in prostate cancer cells.
In aim -3, we will conduct dietary intervention experiments using DIM in Hu-SCID model of human prostate cancer induced by PC-3 human prostate cancer cells. Finally, in aim-4, we will identify gene expression profiles of DIM treated PCa obtained from our Aim-3 using DNA Microarray by interrogating 22, 215 genes (Hu-133A Chip, Affymetrix). These results will be correlated with other molecular targets identified during our preliminary studies using I3C/DIM in cultured PC-3 cells, and also several targets as described under specific aim-2. Collectively, these results will help to identify a comprehensive molecular targets profile of I3C/DIM in prostate cancer that could be further exploited for devising relevant targeted therapy for the prevention and/or treatment of prostate cancer and its metastasis in the future.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-ONC-H (01))
Program Officer
Crowell, James A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wayne State University
Schools of Medicine
United States
Zip Code
Hwang, Clara; Sethi, Seema; Heilbrun, Lance K et al. (2016) Anti-androgenic activity of absorption-enhanced 3, 3'-diindolylmethane in prostatectomy patients. Am J Transl Res 8:166-76
Li, Yiwei; Sarkar, Fazlul H (2016) MicroRNA Targeted Therapeutic Approach for Pancreatic Cancer. Int J Biol Sci 12:326-37
Li, Yiwei; Sarkar, Fazlul H (2016) Role of BioResponse 3,3'-Diindolylmethane in the Treatment of Human Prostate Cancer: Clinical Experience. Med Princ Pract 25 Suppl 2:11-7
Li, Y; Ahmad, A; Sarkar, F H (2015) ASPP and iASPP: Implication in cancer development and progression. Cell Mol Biol (Noisy-le-grand) 61:2-8
Kong, Dejuan; Sethi, Seema; Li, Yiwei et al. (2015) Androgen receptor splice variants contribute to prostate cancer aggressiveness through induction of EMT and expression of stem cell marker genes. Prostate 75:161-74
Li, Yiwei; Go, Vay Liang W; Sarkar, Fazlul H (2015) The Role of Nutraceuticals in Pancreatic Cancer Prevention and Therapy: Targeting Cellular Signaling, MicroRNAs, and Epigenome. Pancreas 44:1-10
Ahmed, Alia; Ali, Shadan; Sarkar, Fazlul H (2014) Advances in androgen receptor targeted therapy for prostate cancer. J Cell Physiol 229:271-6
Ahmad, Aamir; Li, Yiwei; Bao, Bin et al. (2014) Epigenetic regulation of miRNA-cancer stem cells nexus by nutraceuticals. Mol Nutr Food Res 58:79-86
Li, Yiwei; Ahmad, Aamir; Kong, Dejuan et al. (2014) Recent progress on nutraceutical research in prostate cancer. Cancer Metastasis Rev 33:629-40
Li, Yiwei; Ahmad, Aamir; Kong, Dejuan et al. (2013) Targeting MicroRNAs for personalized cancer therapy. Med Princ Pract 22:415-7

Showing the most recent 10 out of 56 publications