Identification of novel targets and the development of commonly used and non-toxic dietary agents for prevention and treatment of prostate cancer (PCa) has become a National Medical Priority. Recent studies have highlighted the role of the transcription factor NFicB in cancer cell survival. Along these lines many studies have shown that NFxB is constitutively activated in human PCa cells and specimens. Thus, NFxB has become an important target for developing novel PCa preventive and therapeutic approaches. Pomegranate derived from the fruit of the tree Punica granatum is known to possess antioxidant and anti-inflammatory properties. We recently showed that pomegranate fruit extract (PFE) inhibited tumor development in mouse skin two stage carcinogenesis model through inhibition of the NFicB signaling pathway. Our unpublished preliminary data showed that PFE is an effective anti-proliferative and pro- apoptotic agent against human PCa PCS cells. On analysis by MALDI-TOF mass spectrometry, PFE was found to contain six anthocyanins and several ellagitannins and hydrolyzable tannins. Our preliminary data showed that among six anthocyanins present in PFE, delphinidin the most abundant was the most effective anti-proliferative agent. Importantly, delphinidin is known to be present in many other pigmented fruits and vegetables like berries, eggplant, dark grapes, tomato, carrots and red onions. The primary objective of this proposal is to capitalize on our novel preliminary findings with delphinidin and PFE in PCa cells and investigate its PCa chemopreventive and/or chemotherapeutic potential under in vitro and in vivo settings. This choice is made because we believe that cell culture studies must be conducted with pure agents rather than a mixture of agents and intervention studies must be conducted with the substances that humans could be persuaded to consume. Using PCa cell lines we will first investigate the cell death cascade activated by delphinidin and understand how it inhibits cell survival signaling mediated by NFicB. In particular using genetic manipulation and pharmacological approaches we will investigate the role of NFicB gene products involved in i) anti-apoptosis (IAP1, xlAP, Bfl-1/A1, Bcl-2, cFLIP, and survivin), ii) proliferation (cyclin D1 and c-Myc), iii) inflammation (Cox-2, PPARy and iNOS) and iv) metastasis (MMP-9, MMP-2 and VEGF). We will then define PCa chemopreventive/therapeutic potential of PFE under in vivo situation using established transgenic and xenograft mouse models. To have relevance to human population, we reasoned that efficacy studies must be conducted in an animal model where disease progression occurs akin to humans. Employing i) TRAMP, a model that mimics progressive forms of human prostatic disease and ii) athymic nude mouse implanted with human PCa cells we will establish the cancer chemopreventive/therapeutic potential of PFE.
This proposal will establish the molecular targets for prostate cancer prevention and treatment and in addition will draw attention to the use of pomegranate and other pigmented fruits and vegetables for prevention against prostate cancer.
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