Prostate cancer prevention by tocopherols

描述（由申请人提供）：前列腺癌（PCa）仍然是美国男性癌症死亡的第二大原因。本申请的长期目标是开发一种有效且安全的策略，用于使用新型的富含γ-生育酚（T）的生育酚混合物（γ-TmT）预防男性PCa。本申请中提出的研究的原理来自于我们已发表和未发表的初步研究，这些研究表明：（i）用γ-TmT治疗显著抑制TRAMP小鼠PCa模型中可触及肿瘤和前列腺上皮内瘤变（PIN）发展的发生率;（ii）γ-TmT对SCID小鼠中LNCaP肿瘤的形成和生长的抑制作用;（iii）γ-TmT处理的TRAMP前列腺肿瘤中Nrf 2和抗氧化应激/抗氧化剂基因的再表达的IHC;（iv）Nrf 2-ARE介导的基因表达的诱导;（v）巨噬细胞中炎症信号传导的抑制;和（vi）LNCaP和PC-3细胞中细胞死亡和凋亡的诱导。尽管有这些有希望的结果，但是，我们对γ-TmT在PCa预防中的分子机制的理解存在重大差距。本项目中提出的研究不仅将填补这些机制空白，而且还将确定γ-TmT在3种动物模型中预防PCa的体内有效性。基于我们的初步研究结果，我们假设γ-TmT治疗选择性地引起前列腺癌细胞中Nrf 2依赖性抗氧化应激反应、抗炎和促凋亡，从而导致前列腺癌发生的化学预防。具体目标：本项目的具体目标是：（1）研究饮食γ-TmT、γ-T、δ-T和α-T对TRAMP和Nrf 2 KO/TRAMP小鼠PCa模型的化学预防作用;（2）确定饮食γ-TmT、γ-T、δ-T和α-T对SCID小鼠LNCaP原位异种移植瘤生长和进展的化学预防作用;（3）检测目的1和2产生的肿瘤样品中的体内癌症预防标志物;（4）阐明T在TRAMP C1、C3、LNCaP和PC-3细胞系中引起的抗肿瘤作用的体外分子机制。硒和维生素E癌症预防试验（SELECT）是一项临床试验，旨在确定这些癌症化学预防物质中的一种或两种是否有助于预防PCa。最近发表的结果表明，硒（200 μg/d）和维生素E（400 IU/d，α-T）单独或共同服用平均5年，不能预防PCa。然而，该试验仅使用α-T，未使用其他T或其组合。这项拟议研究的积极结果将推动高γ-T维生素E（γTmT）膳食补充剂对人类PCa的化学预防功效的临床试验。明确γTmT的抗肿瘤作用机制，阐明γTmT应答的关键生物标志物，将有助于临床试验和优化基于γ TmT的PCa化学预防方案。

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 γ-tocopherol (T) rich mixture of tocopherols (γ-TmT). Rationale for the studies proposed in this application is derived from our published and unpublished preliminary studies demonstrating that: (i) Treatment with γ-TmT significantly suppressed the incidence of palpable tumor and Prostate Intraepithelial Neoplasia (PIN) development in the TRAMP mouse PCa model; (ii) Inhibitory effect of γ-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 γ-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 γ-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 γ-TmT for prevention of PCa in 3 animal models. Based on the results of our preliminary studies, we hypothesize that γ-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 γ-TmT, γ-T, δ-T, and α-T in the TRAMP as well as Nrf2 KO/TRAMP mouse PCa models; (2) Determine the chemopreventive efficacy of dietary γ-TmT, γ-T, δ-T, and α-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 μg/d) and vitamin E (400 IU/d, (α-T), taken alone or together for an average of five years, did not prevent PCa. However, this trial used only α-T and did not use other T or its combination. Positive outcome of this proposed study will drive clinical trials of high γ-T vitamin E (γTmT) dietary supplement for its chemopreventive efficacy against human PCa. Defining the mechanism of anticancer effect of γTmT and to elucidate critical biomarker(s) of γTmT response would potentially be useful in future clinical trials and optimization of γTmT-based chemopreventive regimens against human PCa.