Botanical dietary supplements are used by consumers to prevent and to treat prostate cancer. Recently, an animal prostate cancer model has allowed the safety and efficacy of these supplements to be tested. We have established colonies of TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice, estrogen receptor-deficient (ERaKO and ER(3K0) mice, and ER-deficient mice expressing the TRAMP transgene. Exciting data from our model clearly show that ERaKO mice are highly protected against PDC (poorty differentiated carcinoma) ofthe prostate and ERpKO mice are highly susceptible to PDC. In addition, we recently have found that phytoestrogens, phytosterols, and oxysterols can inhibit hedgehog signaling, a pathway important in prostate cancer. And surprisingly we find that oxysterols can bind ERp 10OX better than ERa with a Kd of ~20nM. Our overall hvpothesis is that differential regulation bv 5 botanicals and their antioxidant/phytoestrogen/phvtosterol components, whose actions are mediated bv 5 kev pathwavs, will be effective in prostate cancer prevention and treatment. The 5 kev pathwavs to be examined are the (anti)oxidant(Nrf2/Keap1 and NADPH oxidase) pathwavs and their interactions with the NF-kappaB-. estrogen-, and hedgehog-signaling pathwavs. Our goals are to characterize responses of key prostate tumor biomarkers to these botanicals and to provide novel molecular mechanisms for these responses useful in conducting later clinical trials.
Aim 1 : Determine in vitro in prostate cancer cell lines the effects ofthe 5 botanicals and selected pure compounds on the activities, protein concentrations, and mRNAs expressed in 5 key pathwavs:
Aim 2 : Perform in vivo cancer prevention trials in single and double transgenic TRAMP mice to test if the cancer protective activity of some pure compounds and botanicals will be dependent upon Keap1/Nrf2 and hedgehog pathway components;
Aim 3 : Test potential active ingredients and complex botanical extracts from Aims #1 or #2 with the same ingredients used in much faster in vivo human xenograft models of prostate cancer;
and Aim 4 : Identify responses associated with cell proliferation, differentiation, apoptosis, and the five key pathways in vivo in prostate tissues in response to botanicals, correlate these responses with tumorigenesis, and continue the correlations with the components ofthe oxidant, inflammatory, hedgehog, and/or estrogen pathways. These studies will provide fundamental insights into prostate tumor biology, and help provide biomarkers to assess the role of these botanicals in modifying the incidence and progression of prostate tumors in humans.

Public Health Relevance

We propose to test for dietary supplements that protect against prostate cancer and to examine the molecular mechanisms involved in this protection, so we can develop novel prostate cancer molecular biomarkers to inform future human clinical trials. We hypothesize that botanical compounds related structurally/functionally to antioxidants, estrogens or hedgehog pathway inhibitors, and also capable of modulating multiple pathways in mouse prostate cancer models, will prevent cancer in humans, as well.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Specialized Center (P50)
Project #
1P50AT006273-01
Application #
8007164
Study Section
Special Emphasis Panel (ZAT1-SM (19))
Project Start
2010-07-01
Project End
2011-06-30
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
1
Fiscal Year
2010
Total Cost
$358,242
Indirect Cost
Name
University of Missouri-Columbia
Department
Type
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
Starkey, Nicholas J E; Li, Yufei; Drenkhahn-Weinaug, Sara K et al. (2018) 27-Hydroxycholesterol Is an Estrogen Receptor ?-Selective Negative Allosteric Modifier of 17?-Estradiol Binding. Endocrinology 159:1972-1981
Johnson, Mitch C; Dela Libera Tres, Matheus; Thomas, Andrew L et al. (2017) Discriminant Analyses of the Polyphenol Content of American Elderberry Juice from Multiple Environments Provide Genotype Fingerprint. J Agric Food Chem 65:4044-4050
Restaino, Robert M; Deo, Shekhar H; Parrish, Alan R et al. (2017) Increased monocyte-derived reactive oxygen species in type 2 diabetes: role of endoplasmic reticulum stress. Exp Physiol 102:139-153
Viswanatharaju Ruddraraju, Kasi; Parsons, Zachary D; Lewis, Calvin D et al. (2017) Allylation and Alkylation of Biologically Relevant Nucleophiles by Diallyl Sulfides. J Org Chem 82:776-780
Ajit, Deepa; Simonyi, Agnes; Li, Runting et al. (2016) Phytochemicals and botanical extracts regulate NF-?B and Nrf2/ARE reporter activities in DI TNC1 astrocytes. Neurochem Int 97:49-56
Johnson, Mitch C; Song, Hailong; Cui, Jiankun et al. (2016) Development of a Method and Validation for the Quantitation of FruArg in Mice Plasma and Brain Tissue Using UPLC-MS/MS. ACS Omega 1:663-668
Mossine, Valeri V; Waters, James K; Chance, Deborah L et al. (2016) Transient Proteotoxicity of Bacterial Virulence Factor Pyocyanin in Renal Tubular Epithelial Cells Induces ER-Related Vacuolation and Can Be Efficiently Modulated by Iron Chelators. Toxicol Sci 154:403-415
Qu, Zhe; Greenlief, C Michael; Gu, Zezong (2016) Quantitative Proteomic Approaches for Analysis of Protein S-Nitrosylation. J Proteome Res 15:1-14
Folk, William R; Smith, Aaron; Song, Hailong et al. (2016) Does Concurrent Use of Some Botanicals Interfere with Treatment of Tuberculosis? Neuromolecular Med 18:483-6
Mudge, Elizabeth; Applequist, Wendy L; Finley, Jamie et al. (2016) Variation of Select Flavonols and Chlorogenic Acid Content of Elderberry Collected Throughout the Eastern United States. J Food Compost Anal 47:52-59

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