Prostate cancer (PCa) is the most common malignancy in men; it mostly targets men aged around 45 and older and is a leading cause of cancer mortality among males in the United States. Despite the decades of research and treatment advances, androgen withdrawal is the only effective therapy for patients with advanced malignancy. However, prolonged androgen deprivation generally results in disease relapse and ultimately leads to androgen-independent tumor growth in almost all patients. Inositol hexaphosphate (IP6) is mostly present in high-fiber diets, is also consumed as dietary supplement to lower high cholesterol levels and for the prevention of heart and liver diseases. Reports from our group and others show that IP6 modulates cell proliferation, differentiation and apoptosis in various PCa cells and in vivo xenograft growth without any toxicity; however, none of these studies have examined in detail the mechanisms and targets of IP6 efficacy related to phosphoinositide 3-kinase (PI3K)/Akt pathway. Deregulation of the PI3K/Akt pathway is central in the transmission of growth regulatory signals originating from cell surface receptors and modulates proliferation, angiogenesis and apoptosis of PCa cells. Accordingly, here we assessed the efficacy of IP6 on highly invasive human PCa PC3 cells with respect to the role of PI3K/Akt signaling cascade. IP6 treatment at 2mM dose suppressed cell proliferation, induced the levels of caspase 3 and PARP cleavage, and inhibited constitutive activation of Akt and its upstream targets PI3K, phosphoinositide-dependent kinase-1 at Serine241 and integrin linked kinase (ILK). Downstream of Akt, IP6 inhibited the phosphorylation of glycogen synthase kinase-3\#945;/\#946; at Serine21/9 and consequently reduced the expression of cyclin D1. Next we assessed the in vivo effect of 1 and 2% IP6 feeding in drinking water (weight/volume) on PC3 tumor xenograft growth in athymic nude mice, where a dose of 2% IP6 strongly inhibited tumor growth by 52% (P < 0.001) and tumor weight by 59% (P < 0.001). Molecular analyses of tumors showed a significant decrease in the levels and/or activation of cell survival/proliferation (ILK, phosphorylated Akt, cyclin D1, proliferating cell nuclear antigen) and angiogenesis (cluster of differentiation molecule 31, vascular endothelial growth factor, endothelial nitric oxide synthase and hypoxia-inducible factor-1\#945;) regulators but an increase in the apoptotic markers (caspase 3 and PARP cleavage) in IP6-treated PC3 tumor xenografts compared to water control. Together, these findings suggest that by targeting PI3K/Akt/GSK-3\#945;/\#946; pathway, IP6 suppresses survival/proliferation, angiogenesis and induces tumor cell death, which might have potential implications in controlling advanced and aggressive PCa where conventional chemotherapy has limitations.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2972.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009