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.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Project (R01)
Project #
5R01AT002709-03
Application #
7285702
Study Section
Special Emphasis Panel (ZRG1-CDP (01))
Program Officer
Sorkin, Barbara C
Project Start
2005-09-15
Project End
2010-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
3
Fiscal Year
2007
Total Cost
$265,530
Indirect Cost
Name
Case Western Reserve University
Department
Urology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Shukla, Sanjeev; Bhaskaran, Natarajan; Babcook, Melissa A et al. (2014) Apigenin inhibits prostate cancer progression in TRAMP mice via targeting PI3K/Akt/FoxO pathway. Carcinogenesis 35:452-60
Shukla, Sanjeev; Fu, Pingfu; Gupta, Sanjay (2014) Apigenin induces apoptosis by targeting inhibitor of apoptosis proteins and Ku70-Bax interaction in prostate cancer. Apoptosis 19:883-94
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Kanwal, Rajnee; Pandey, Mitali; Bhaskaran, Natarajan et al. (2014) Protection against oxidative DNA damage and stress in human prostate by glutathione S-transferase P1. Mol Carcinog 53:8-18
Shukla, Sanjeev; Bhaskaran, Natarajan; Maclennan, Gregory T et al. (2013) Deregulation of FoxO3a accelerates prostate cancer progression in TRAMP mice. Prostate 73:1507-17
Bhaskaran, Natarajan; Srivastava, Janmejai K; Shukla, Sanjeev et al. (2013) Chamomile confers protection against hydrogen peroxide-induced toxicity through activation of Nrf2-mediated defense response. Phytother Res 27:118-25
Bhaskaran, Natarajan; Shukla, Sanjeev; Kanwal, Rajnee et al. (2012) Induction of heme oxygenase-1 by chamomile protects murine macrophages against oxidative stress. Life Sci 90:1027-33
Babcook, Melissa A; Gupta, Sanjay (2012) Apigenin Modulates Insulin-like Growth Factor Axis: Implications for Prevention and Therapy of Prostate Cancer. Curr Drug Targets :
Pandey, Mitali; Kaur, Parminder; Shukla, Sanjeev et al. (2012) Plant flavone apigenin inhibits HDAC and remodels chromatin to induce growth arrest and apoptosis in human prostate cancer cells: in vitro and in vivo study. Mol Carcinog 51:952-62

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