Prostate cancer prevention by tocopherols

描述(申请人提供)：前列腺癌(PCA)仍然是美国男性癌症死亡的第二大原因。这项应用的长期目标是开发一种有效且安全的策略，使用一种新型的富含生育酚(？-TMT)的生育酚(？-TMT)预防男性前列腺癌。本申请中提出的研究的基本原理来自我们已发表和未发表的初步研究表明：(I)？-TMT治疗显著抑制可触及的肿瘤的发生率和前列腺癌上皮内瘤(PIN)的发展；(Ii)？-TMT对SCID小鼠LNCaP肿瘤的形成和生长的抑制作用；(Iii)？-TMT治疗的不稳定的前列腺肿瘤中Nrf2的再表达和抗氧化应激/抗氧化基因的IHC；(Iv)诱导Nrf2-ARE介导的基因表达；(V)抑制巨噬细胞中的炎症信号；诱导LNCaP和PC-3细胞死亡和凋亡。然而，尽管有这些可喜的结果，我们对？-TMT预防前列腺癌的分子机制(S)的理解仍然存在重大差距。本项目提出的研究不仅将填补这些机制空白，而且还将确定？-TMT在3种动物模型中预防前列腺癌的体内效果。根据我们的初步研究结果，我们假设？-TMT治疗选择性地在前列腺癌细胞中引起Nrf2依赖的抗氧化应激反应以及抗炎和促凋亡，从而达到化学预防前列腺癌的目的。具体目标：本项目的具体目标是：(1)研究饮食中？-TMT、？-T、(-T)和(-T)对TRAMP和Nrf2 KO/TraMP小鼠PCA模型的化学预防效果；(2)确定饮食？-TMT、？-T、(-T)和(-T)对SCID小鼠LNCaP原位移植瘤生长和进展的化学预防效果；(3)检测AIMS 1和2产生的肿瘤标本中的体内肿瘤预防标志物；(4)阐明T对TRAMP C1、C3、LNCaP和PC-3细胞株的体外抗肿瘤作用的分子机制。拟议研究的意义：硒和维生素E癌症预防试验(SELECT)，这是一项临床试验，旨在确定当作为膳食补充剂服用时，这两种癌症化学预防物质中的一种或两种是否可以帮助预防前列腺癌。最近公布的结果表明，单独或同时服用硒(200g/d)和维生素E(400IU/d，-T)平均五年不能预防前列腺癌。然而，这项试验只使用了(-T，没有使用其他T或其组合。这项拟议研究的积极结果将推动高T维生素E(？TMT)膳食补充剂的临床试验，以证明其对人类前列腺癌的化学预防效果。明确TMT的抗癌作用机制，阐明TMT反应的关键生物标记物S，对今后的临床试验和基于TMT的人前列腺癌化学预防方案的优化具有重要意义。

DESCRIPTION (provided by applicant): 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 Rationale for the studies proposed in this application is derived from our published and unpublished preliminary studies demonstrating that: (i) Treatment with ?-TmT significantly suppressed the incidence of palpable tumor and Prostate Intraepithelial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.