In recent studies, we found that grape seed extract (GSE) significantly inhibits DU145 xenograft growth in nude mice. Mechanistic studies showed that GSE inhibits erbB1-ERKI/2-AP1 and NF-kB activation, b) alters cell cycle regulators and c) activates caspases, and that these events are associated with human prostate cancer (PCA) DU145 cell growth inhibition, G1 arrest and apoptotic death. In an attempt to conduct detailed mechanistic studies with active compound in GSE, we were able to isolate procyanidin B3 that showed even stronger DU145 cell growth inhibitory, and S and/or G2-M arrest and apoptotic death inducing efficacy than GSE in DU145 cells. In this grant, we propose in depth mechanistic followed by tumor efficacy studies with procyanidin B3 in cell culture and tumor xenograffs. The central hypothesis is that procyanidin B3 inhibits a) mitogenic and cell survival signaling, b) induces S and/or G2-M arrest depending on its concentration via alteration in cell cycle regulators, and c) causes apoptosis via inhibition of survival signal, mitochondrial damage and Caspases activation. Collectively, these effects lead to its preventive and therapeutic efficacy against PCA. Following specific aims are proposed that will utilize normal human prostate epithelial and PCA LNCaP and DU145 cells. 1) To assess and define the effect of procyanidin B3 on mitogenic and cell survival signaling. 2) To assess and define the effect of procyanidin B3 on S and G2-M cell cycle regulators. 3) To assess and define the effect of procyanidin B3 on apoptosis regulators. 4) To assess and establish the efficacy of procyanidin B3 in nude mice tumor xenografts. 5) To continue identification of biologically active fraction(s) in GSE, and characterize individual compounds present therein. As a practical and translational approach, outcome of the proposed studies will form a basis for additional studies in pre-clinical PCA models followed by clinical trials in PCA patients to further define and establish the preventive and therapeutic efficacy of procyanidin B3 isolated from GSE.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA091883-05
Application #
7174782
Study Section
Special Emphasis Panel (ZRG1-PTHB (02))
Program Officer
Parnes, Howard L
Project Start
2003-02-14
Project End
2008-06-30
Budget Start
2007-01-01
Budget End
2008-06-30
Support Year
5
Fiscal Year
2007
Total Cost
$322,524
Indirect Cost
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Kumar, Rahul; Deep, Gagan; Wempe, Michael F et al. (2018) Procyanidin B2 3,3?-di-O-gallate induces oxidative stress-mediated cell death in prostate cancer cells via inhibiting MAP kinase phosphatase activity and activating ERK1/2 and AMPK. Mol Carcinog 57:57-69
Reed, Dominique; Raina, Komal; Agarwal, Rajesh (2018) Nutraceuticals in prostate cancer therapeutic strategies and their neo-adjuvant use in diverse populations. NPJ Precis Oncol 2:15
Shrotriya, Sangeeta; Tyagi, Alpna; Deep, Gagan et al. (2015) Grape seed extract and resveratrol prevent 4-nitroquinoline 1-oxide induced oral tumorigenesis in mice by modulating AMPK activation and associated biological responses. Mol Carcinog 54:291-300
Kumar, Rahul; Deep, Gagan; Wempe, Michael F et al. (2015) Procyanidin B2 3,3?-di-O-gallate inhibits endothelial cells growth and motility by targeting VEGFR2 and integrin signaling pathways. Curr Cancer Drug Targets 15:14-26
Shrotriya, Sangeeta; Deep, Gagan; Lopert, Pamela et al. (2015) Grape seed extract targets mitochondrial electron transport chain complex III and induces oxidative and metabolic stress leading to cytoprotective autophagy and apoptotic death in human head and neck cancer cells. Mol Carcinog 54:1734-47
Tyagi, Alpna; Raina, Komal; Shrestha, Suraj Prakash et al. (2014) Procyanidin B2 3,3(?)-di-O-gallate, a biologically active constituent of grape seed extract, induces apoptosis in human prostate cancer cells via targeting NF-?B, Stat3, and AP1 transcription factors. Nutr Cancer 66:736-46
Ting, Harold; Deep, Gagan; Agarwal, Chapla et al. (2014) The strategies to control prostate cancer by chemoprevention approaches. Mutat Res 760:1-15
Tyagi, Alpna; Raina, Komal; Gangar, Subhash et al. (2013) Differential effect of grape seed extract against human non-small-cell lung cancer cells: the role of reactive oxygen species and apoptosis induction. Nutr Cancer 65 Suppl 1:44-53
Raina, Komal; Tyagi, Alpna; Kumar, Dileep et al. (2013) Role of oxidative stress in cytotoxicity of grape seed extract in human bladder cancer cells. Food Chem Toxicol 61:187-95
Shrotriya, Sangeeta; Gagan, Deep; Ramasamy, Kumaraguruparan et al. (2012) Poly[3-(3, 4-dihydroxyphenyl) glyceric acid] from Comfrey exerts anti-cancer efficacy against human prostate cancer via targeting androgen receptor, cell cycle arrest and apoptosis. Carcinogenesis 33:1572-80

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