? ? It is estimated that 234,460 new prostate cancer cases will be diagnosed and approximately 27,350 prostate cancer-related deaths are predicted in the US alone in the year 2006. Persistence of isolated cancer cells (even after surgery and androgen-ablation therapy), their proliferation, androgen-independence and invasion to distant sites is the major cause of deaths in human prostate cancer patients. Aberration in the levels and functioning of multiple proteins or molecular pathways including beta catenin, nuclear factor kappa B and phosphotidyl inositol 3 kinase /Akt signaling network, has been associated with the androgen-independence, proliferation, invasion and chemoresistance of prostate cancer cells. Since most of the chemotherapeutic agents generally target a specific protein or a molecular pathway, they most often fail to inhibit the growth of advanced prostate cancer in preclinical and clinical settings. Thus, it is important to identify novel agents with an ability to target multiple molecular pathways. It is increasingly appreciated that chemoprevention through diet-based natural agents could be an effective approach to prevent and treat prostate cancer in humans. Based on our published studies and preliminary data, we believe that Lupeol, a non-nutrient and non-toxic natural agent present in strawberry, grapes, mango, figs, olive and vegetables, could be an ideal chemopreventive and therapeutic agent with an ability to act on multiple molecular pathways. We hypothesize that Lupeol has the potential to kill highly aggressive and chemoresistant prostate cancer cells while sparing normal cells, inhibit their proliferation and invasion through the modulation of beta catenin, nuclear factor kappa B and phosphotidyl inositol 3 kinase /Akt signaling network. It is important to emphasize that, consistent with current NCI opinion, the term """"""""chemoprevention"""""""" is used in its broadest sense in this application, i.e. in a partially therapeutic as well as purely preventive context. To achieve our goal, we propose two specific aims: (1) to investigate the anti-proliferative potential of Lupeol against androgen-independent prostate cancer cells, and to define its mechanism of action under cell culture conditions and (2) to investigate whether Lupeol possesses the chemopreventive and/or chemotherapeutic effects against the tumorigenicity of androgen-insensitive prostate cancer cells in an animal model. We believe that this application will be extremely valuable in providing a novel fruit and vegetable based agent for chemoprevention and possibly for treating prostate cancer ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
5R03CA130064-02
Application #
7472599
Study Section
Special Emphasis Panel (ZCA1-SRRB-F (M1))
Program Officer
Perloff, Marjorie
Project Start
2007-08-01
Project End
2010-07-31
Budget Start
2008-08-01
Budget End
2010-07-31
Support Year
2
Fiscal Year
2008
Total Cost
$73,500
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
Siddique, Hifzur Rahman; Nanda, Sanjeev; Parray, Aijaz et al. (2012) Androgen receptor in human health: a potential therapeutic target. Curr Drug Targets 13:1907-16
Siddique, Hifzur Rahman; Saleem, Mohammad (2011) Beneficial health effects of lupeol triterpene: a review of preclinical studies. Life Sci 88:285-93
Saleem, Mohammad; Murtaza, Imtiyaz; Tarapore, Rohinton S et al. (2009) Lupeol inhibits proliferation of human prostate cancer cells by targeting beta-catenin signaling. Carcinogenesis 30:808-17
Saleem, Mohammad (2009) Lupeol, a novel anti-inflammatory and anti-cancer dietary triterpene. Cancer Lett 285:109-15
Saleem, Mohammad; Murtaza, Imtiyaz; Witkowsky, Olya et al. (2009) Lupeol triterpene, a novel diet-based microtubule targeting agent: disrupts survivin/cFLIP activation in prostate cancer cells. Biochem Biophys Res Commun 388:576-82
Murtaza, Imtiyaz; Saleem, Mohammad; Adhami, Vaqar Mustafa et al. (2009) Suppression of cFLIP by lupeol, a dietary triterpene, is sufficient to overcome resistance to TRAIL-mediated apoptosis in chemoresistant human pancreatic cancer cells. Cancer Res 69:1156-65
Saleem, Mohammad; Maddodi, Nityanand; Abu Zaid, Mohammad et al. (2008) Lupeol inhibits growth of highly aggressive human metastatic melanoma cells in vitro and in vivo by inducing apoptosis. Clin Cancer Res 14:2119-27