Prostate cancer (PCA) is a major health problem and currently there are no effective strategies available for its management indicating the need for effective chemopreventive agents. Preliminary studies from our laboratory indicate that Nexrutine(TM) (NPS00299), a non-toxic over the counter anti-inflammatory agent inhibits the growth of androgen-responsive (LNCaP) human prostate cancer cells and mouse prostate cells (TRAMP C1 and C2; transgenic adenocarcinoma of mouse prostate) representing different stages of progression. Treatment of LNCaP cells with Nexrutine(TM) induced apoptosis; reduced the levels of phosphorylated Akt, PDK-1 (that phosphorylates Akt on Thr 308); p65 component of transcription factor NF-kappaB in LNCaP cells. Further, Cox-2 levels became undetectable in LNCaP cells following Nexrutine(TM) treatment. The objective of this pilot proposal is to assess Nexrutine(TM) preclinically for its use as a potent prostate cancer chemopreventive agent in the TRAMP model and to determine the molecular mechanism that underlies its efficacy using human prostate cancer cells as well as in tumors from TRAMP mice. We have proposed two specific aims to investigate this objective; 1: Identify the most effective dose of Nexrutine(TM) that produces maximal activity for its use as a preventive agent using TRAMP model. We will assess the potential preventive effects of Nexrutine(TM) on development of tumors, latency period, size and number of tumors and metastatic spread. In addition we will validate the use of apoptotic, Akt and NFkappaB signaling components identified from mechanistic studies proposed in Specific aim 2 as intermediate markers of Nexrutine(TM) 's action in prostate tumors following feeding with Nexrutine(TM); 2: Explore the role of Akt, NF-kappaB and Cox-2 in mediating Nexrutine(TM)-induced apoptosis. We will further examine the mechanism of Nexrutine(TM) -induced apoptosis in human prostate cancer cell lines and dissect the precise role of Akt and NF-kappaB and Cox-2 in this process. The novelty of the current pilot project is that it tests the concept of the use of a cheaply available dietary supplement (complementary and alternate medicine) in preventing the development of prostate cancer through modulation of key components of the cell survival signaling pathway. Since the development and progression of PCA in this pre-clinical model histologically resembles human PCA development, the results obtained from this study can be extrapolated to conduct clinical trials that will eventually be useful for preventing human prostate cancer.
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