Epidemiological studies and clinical observations suggest that persistent chronic inflammation is important in prostate carcinogenesis. The reactive oxygen and nitrogen species released from inflammatory cells induce oxidative stress in the proliferating epithelium that could directly interact with DNA to produce permanent genomic alterations and/or play critical role as regulatory mediators in signaling processes by activating transcription factor complex, NFkappaB. Members of the Rel/NF-kappaB family control important network of genes that influence cell proliferation, inflammation, cellular adhesion, apoptosis and adaptive responses to changes in cellular redox balance. Aberrant NFkappaB activation has been implicated in the pathogenesis of several human malignancies. Our recent studies (Neoplasia Vol.6 No.4, 2004) have shown that NF-kappaB/p65 is constitutively activated in human prostate adenocarcinoma and correlates with disease progression. Based on these interesting findings we suggest NF-kappaB signaling pathway as a key molecular target for the development of preventive and/or therapeutic strategies against prostate cancer. The present proposal capitalizes on these novel findings and is designed to investigate the antiinflammatory, antioxidant and cancer chemopreventive potential of chamomile, a common herb used as folk medicine, by targeting NF-kappaB signaling pathway. Recent interest in the development of chamomile as complementary and alternative medicine (CAM) for prostate cancer is due to its anti-inflammatory, antioxidant and mild sedative properties. Chamomile is one of the most popular herbs consumed in the form of tea equivalent to over one million cups per day.
The specific aims 1 -4 will investigate the molecular mechanism(s) of chamomile that can directly lead to inhibition of NF-kappaB and its responsive genes important in prostate cancer progression (cyclin D1, Bcl2, BclxL, IL-6, IL-8, MMP- 9, and PAR4); and/or indirectly through i) ROS production, ii) transcriptional regulation of inflammatory genes (COX-2 and NOS-2), iii) transactivation of gamma-glutamylcysteine synthetase promoter, and iv) Nrf2/ARE-dependent detoxification in both androgen sensitive- and insensitive- human prostate carcinoma cells. We will also investigate how chamomile can mediate these effects through down-regulation of NF-kappaB by analyzing levels and activity of key kinase molecules and associated mechanisms that are involved in the NF-kappaB signaling pathway. Moreover, we will employ genetic (over-expression and suppression.techniques) and pharmacological (inhibitors) approaches to delineate whether the effects of chamomile are directly mediated by the down regulation of NF-kappaB. These results will be compared to those obtained from normal human prostate epithelial cells. Additionally, we also propose to test the cancer chemopreventive potential of chamomile in a well established transgenic mouse model, TRAMP that exhibit significantly higher constitutive NF-kappaB/p65 expression during prostate cancer progression. Completion of the proposed studies will provide a 'head start' to initiate clinical trials in prostate cancer patients and/or high-risk individuals.
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