The central focus of this grant is to generate critical pre-clinical efficacy and mechanism data with IP6 in various available prostate cancer (PCA) animal models that would set the stage for clinical trials in humans suffering with PCA, which is the most frequently diagnosed invasive malignancy and second most common cause of cancer deaths in males in the United States. Overall, PCA growth and progression involve an aberrant cell cycle progression following gradual accumulation of genetic and epigenetic changes over a period of years. Several mechanisms including a decrease in and/or loss of cyclin-dependent kinase inhibitor (CDKI) function contribute to these events, suggesting that an induction in CDKI level and/or gain in its function is one of the most promising approaches for PCA prevention, growth control and/or therapy. Inositol hexaphosphate (IP6) is a nutrient constituting 6.4% (w/w) or even higher levels in most cereals, legumes, nuts, oil seeds and soybean, and also taken orally as an over-the-counter dietary/nutrient supplement for its several health benefits without any known toxicity. In our recent studies, we found that oral feeding of IP6 to nude mice inhibits the growth of human PCA xenograft without toxicity; completed pilot study in TRAMP model also showed prevention in prostate tumorigenesis by IP6. In PCA cell culture, completed studies by us show that IP6 up- regulates CDKI Kip1/p27 and Cip1/p21 levels together with their increased interaction with CDKs causing inhibition in the kinase activity of CDKs and associated cyclins. These effects of IP6 also caused a G1 arrest, strong inhibition of human and rodent PCA cell growth, and induction of their apoptotic death. No such IP6 effects were observed, however, in non-neoplastic human prostate epithelial cells. Additional studies with siRNA showed that IP6-caused G1 arrest in DU145 cells requires up-regulation of p27 and p21. We also observed that IP6 inhibits PI3K-Akt and NF-KB activation in DU145 cells. Based on these studies, our hypothesis is that p27 and p21 induction is required for cell cycle arrest and in part apoptotic death, together with inhibition of PI3K/Akt/NF-kB activation, by IP6 in its cancer chemopreventive efficacy against PCA. To test this hypothesis, we will: 1) Examine IP6 as a preventive agent in mouse TRAMP and MNU-testosterone rat PCA models; II) Examine efficacy of IP6 in growth control and therapy of PCA using ectopic and orthotopic human prostate carcinoma xenografts in male nude mice; III) Define and characterize in vivo efficacy of IPS on cell cycle regulators in tumor tissues, identify and establish CDKI induction as a molecular target of IP6 action using both cell culture and animal models, and define the mechanism of CDKI induction by IP6 in cell culture; and IV) Define and characterize the in vivo efficacy of IP6 on apoptotic pathways, and identify and establish the role of CDKI, and PI3K-Akt and NF-KB pathways in IPG-induced apoptosis using cell culture systems. Overall, proposed studies would further establish preventive and interventive efficacy of IP6 against PCA and define its molecular mechanisms on cell cycle and apoptosis regulation.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Chemo/Dietary Prevention Study Section (CDP)
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Kim, Young S
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University of Colorado Denver
Schools of Pharmacy
United States
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Reed, Dominique; Raina, Komal; Agarwal, Rajesh (2018) Nutraceuticals in prostate cancer therapeutic strategies and their neo-adjuvant use in diverse populations. NPJ Precis Oncol 2:15
Raina, Komal; Ravichandran, Kameswaran; Rajamanickam, Subapriya et al. (2013) Inositol hexaphosphate inhibits tumor growth, vascularity, and metabolism in TRAMP mice: a multiparametric magnetic resonance study. Cancer Prev Res (Phila) 6:40-50
Jain, Anil K; Raina, Komal; Agarwal, Rajesh (2013) Deletion of p21/Cdkn1a confers protective effect against prostate tumorigenesis in transgenic adenocarcinoma of the mouse prostate model. Cell Cycle 12:1598-604
Gu, Mallikarjuna; Raina, Komal; Agarwal, Chapla et al. (2010) Inositol hexaphosphate downregulates both constitutive and ligand-induced mitogenic and cell survival signaling, and causes caspase-mediated apoptotic death of human prostate carcinoma PC-3 cells. Mol Carcinog 49:1-12
Roy, Srirupa; Gu, Mallikarjuna; Ramasamy, Kumaraguruparan et al. (2009) p21/Cip1 and p27/Kip1 Are essential molecular targets of inositol hexaphosphate for its antitumor efficacy against prostate cancer. Cancer Res 69:1166-73
Gu, Mallikarjuna; Roy, Srirupa; Raina, Komal et al. (2009) Inositol hexaphosphate suppresses growth and induces apoptosis in prostate carcinoma cells in culture and nude mouse xenograft: PI3K-Akt pathway as potential target. Cancer Res 69:9465-72
Roy, Srirupa; Singh, Rana P; Agarwal, Chapla et al. (2008) Downregulation of both p21/Cip1 and p27/Kip1 produces a more aggressive prostate cancer phenotype. Cell Cycle 7:1828-35
Agarwal, Rajesh; Deep, Gagan (2008) Kava, a tonic for relieving the irrational development of natural preventive agents. Cancer Prev Res (Phila Pa) 1:409-12
Ramasamy, Kumaraguruparan; Agarwal, Rajesh (2008) Multitargeted therapy of cancer by silymarin. Cancer Lett 269:352-62
Deep, Gagan; Agarwal, Rajesh (2008) New combination therapies with cell-cycle agents. Curr Opin Investig Drugs 9:591-604

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