Prostate cancer (PCa) remains the second leading cause of cancer death in men in the United States. The long term goal of this application is to develop an effective and safe strategy for prevention of PCa in men using a novel high (-tocopherol (T) rich mixture of tocopherols (?-TmT). Rationale for the studies proposed in this application is derived from our published and unpublished preliminary studies demonstrating that: (i) Treatment with ?-TmT significantly suppressed the incidence of palpable tumor and Prostate Intraepithelial Neoplasia (PIN) development in the TRAMP mouse PCa model;(ii) Inhibitory effect of ?-TmT on the formation and growth of LNCaP tumors in the SCID mice;(iii) IHC of re-expression of Nrf2 and anti-oxidative stress/antioxidant genes in ?-TmT-treated TRAMP prostate tumors;(iv) Induction of Nrf2-ARE-mediated gene expression;(v) Inhibition of inflammatory signaling in macrophages;and (vi) Induction of cell death and apoptosis in LNCaP and PC-3 cells. Despite these promising results, however, significant gaps in our understanding of the molecular mechanism(s) of ?-TmT exist in PCa prevention. Studies proposed in this project will not only fill these mechanistic gaps but also determine the in vivo efficacy of ?-TmT for prevention of PCa in 3 animal models. Based on the results of our preliminary studies, we hypothesize that ?-TmT treatment selectively causes Nrf2-dependent anti-oxidative stress response and anti-inflammatory and pro-apoptosis in prostate cancer cells leading to chemoprevention of prostate carcinogenesis.
Specific Aims :
The specific aims of this project are to: (1) Investigate the chemopreventive efficacy of dietary ?-TmT, ?-T, (-T, and (-T in the TRAMP as well as Nrf2 KO/TRAMP mouse PCa models;(2) Determine the chemopreventive efficacy of dietary ?-TmT, ?-T, (-T, and (-T on the growth and progression of LNCaP orthotopic xenograft tumors in SCID mice;(3) Examine the in vivo cancer preventive markers in the tumor samples generated from Aims 1 and 2;(4) Elucidate the in vitro molecular mechanisms of anti-tumor effects elicited by T in TRAMP C1, C3, LNCaP and PC-3 cell lines. Significance of the Proposed Research: Selenium and Vitamin E Cancer Prevention Trial (SELECT), a clinical trial to determine if one or both of these cancer chemopreventive substances can help prevent PCa when taken as dietary supplements. The recently published results indicated that selenium (200 ?g/d) and vitamin E (400 IU/d, (-T), taken alone or together for an average of five years, did not prevent PCa. However, this trial used only (-T and did not use other T or its combination. Positive outcome of this proposed study will drive clinical trials of high ?-T vitamin E (?TmT) dietary supplement for its chemopreventive efficacy against human PCa. Defining the mechanism of anticancer effect of ?TmT and to elucidate critical biomarker(s) of ?TmT response would potentially be useful in future clinical trials and optimization of ?TmT-based chemopreventive regimens against human PCa.
Prostate cancer (PCa) remains the second leading cause of cancer death in men in the US. The long term goal of this application is to develop an effective and safe strategy for prevention of PCa in men using a novel high content of ? mixed tocopherols (?-TmT), particularly in view of the recent failure of the SELECT trial.
|Yang, Yuqing; Yang, Irene; Cao, Mingnan et al. (2018) Fucoxanthin Elicits Epigenetic Modifications, Nrf2 Activation and Blocking Transformation in Mouse Skin JB6 P+ Cells. AAPS J 20:32|
|Huang, Ying; Wu, Renyi; Su, Zheng-Yuan et al. (2017) A naturally occurring mixture of tocotrienols inhibits the growth of human prostate tumor, associated with epigenetic modifications of cyclin-dependent kinase inhibitors p21 and p27. J Nutr Biochem 40:155-163|
|Yang, Yuqing; Fuentes, Francisco; Shu, Limin et al. (2017) Epigenetic CpG Methylation of the Promoter and Reactivation of the Expression of GSTP1 by Astaxanthin in Human Prostate LNCaP Cells. AAPS J 19:421-430|
|Cao, Mingnan; Wang, Huixia; Guo, Limei et al. (2017) Dibenzoylmethane Protects Against CCl4-Induced Acute Liver Injury by Activating Nrf2 via JNK, AMPK, and Calcium Signaling. AAPS J 19:1703-1714|
|Boyanapalli, Sarandeep S S; Li, Wenji; Fuentes, Francisco et al. (2016) Epigenetic reactivation of RASSF1A by phenethyl isothiocyanate (PEITC) and promotion of apoptosis in LNCaP cells. Pharmacol Res 114:175-184|
|Cheng, David; Wu, Renyi; Guo, Yue et al. (2016) Regulation of Keap1-Nrf2 signaling: The role of epigenetics. Curr Opin Toxicol 1:134-138|
|Li, Wenji; Guo, Yue; Zhang, Chengyue et al. (2016) Dietary Phytochemicals and Cancer Chemoprevention: A Perspective on Oxidative Stress, Inflammation, and Epigenetics. Chem Res Toxicol 29:2071-2095|
|Yang, Anne Yuqing; Kim, Hyuck; Li, Wenji et al. (2016) Natural compound-derived epigenetic regulators targeting epigenetic readers, writers and erasers. Curr Top Med Chem 16:697-713|
|Guo, Yue; Su, Zheng-Yuan; Kong, Ah-Ng Tony (2015) Current Perspectives on Epigenetic Modifications by Dietary Chemopreventive and Herbal Phytochemicals. Curr Pharmacol Rep 1:245-257|
|Zhang, Chengyue; Shu, Limin; Kong, Ah-Ng Tony (2015) MicroRNAs: New players in cancer prevention targeting Nrf2, oxidative stress and inflammatory pathways. Curr Pharmacol Rep 1:21-30|
Showing the most recent 10 out of 23 publications