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 Our unpublished preliminary data showed that PFE is an effective anti-proliferative and pro- apoptotic agent against human PCa PCS cells.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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA120451-04
Application #
7754389
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Perloff, Marjorie
Project Start
2007-01-01
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
4
Fiscal Year
2010
Total Cost
$279,300
Indirect Cost
Name
University of Wisconsin Madison
Department
Dermatology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Khan, Naghma; Mukhtar, Hasan (2013) Modulation of signaling pathways in prostate cancer by green tea polyphenols. Biochem Pharmacol 85:667-72
Khan, Naghma; Mukhtar, Hasan (2013) Tea and health: studies in humans. Curr Pharm Des 19:6141-7
Syed, Deeba N; Chamcheu, Jean-Christopher; Adhami, Vaqar M et al. (2013) Pomegranate extracts and cancer prevention: molecular and cellular activities. Anticancer Agents Med Chem 13:1149-61
Tarapore, Rohinton S; Siddiqui, Imtiaz A; Adhami, Vaqar M et al. (2013) The dietary terpene lupeol targets colorectal cancer cells with constitutively active Wnt/β-catenin signaling. Mol Nutr Food Res 57:1950-8
Khan, Naghma; Syed, Deeba N; Ahmad, Nihal et al. (2013) Fisetin: a dietary antioxidant for health promotion. Antioxid Redox Signal 19:151-62
Khan, Naghma; Afaq, Farrukh; Khusro, Fatima H et al. (2012) Dual inhibition of phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin signaling in human nonsmall cell lung cancer cells by a dietary flavonoid fisetin. Int J Cancer 130:1695-705
Adhami, Vaqar Mustafa; Siddiqui, Imtiaz Ahmad; Syed, Deeba N et al. (2012) Oral infusion of pomegranate fruit extract inhibits prostate carcinogenesis in the TRAMP model. Carcinogenesis 33:644-51
Khan, Naghma; Adhami, Vaqar M; Afaq, Farrukh et al. (2012) Butein induces apoptosis and inhibits prostate tumor growth in vitro and in vivo. Antioxid Redox Signal 16:1195-204
Asim, Mohammad; Hafeez, Bilal Bin; Siddiqui, Imtiaz Ahmad et al. (2011) Ligand-dependent corepressor acts as a novel androgen receptor corepressor, inhibits prostate cancer growth, and is functionally inactivated by the Src protein kinase. J Biol Chem 286:37108-17
Siddiqui, Imtiaz A; Asim, Mohammad; Hafeez, Bilal B et al. (2011) Green tea polyphenol EGCG blunts androgen receptor function in prostate cancer. FASEB J 25:1198-207

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