Curcuma Longa: epigenetic effects in prostate and colon cancer

性状（由申请人提供）：姜黄（Curcuma longa（C.L.））根的产物，通常含有三种主要成分，姜黄素（CUR;约77%），脱甲氧基姜黄素（约17%）和双脱甲氧基姜黄素（约3%），它们通常用作植物性膳食补充剂。本研究项目的长期目标是开发一种安全有效的使用C. L.在预防疾病，包括前列腺癌（PCa）和结直肠癌（CRC）在美国。PCa仍然是美国男性中最常见的恶性肿瘤，2009年预计有192，280例新发病例和27，360例死亡，而CRC是40至79岁男性癌症死亡的第二大常见原因，并且是女性癌症死亡的第三大原因，2010年诊断出估计有53，439例新发病例。在本申请中提出的研究的基本原理源自我们已发表的以及未发表的初步研究，其证明：（1）在PCa中，CUR显示出对裸鼠人PC-3异种移植物和TRAMP小鼠中前列腺肿瘤的体内抑制;（2）在CRC中，CUR诱导人HT-29结肠癌细胞的凋亡并抑制NF κ B; CUR二苯甲酰甲烷的类似物，抑制APCmin小鼠中的腺瘤和AOM-DSS小鼠中的CRC;（3）CUR调节使用Nrf 2 KO小鼠的肠中的Nrf 2依赖性基因;（4）随着TRAMP小鼠PCa的进展，存在抗氧化应激转录因子Nrf 2和Nrf 2靶基因的丢失;（5）用CUR喂养TRAMP小鼠导致TRAMP前列腺肿瘤中Nrf 2和Nrf 2靶基因UGT 1A 1的重新表达，与肿瘤抑制相关;（6）Nrf 2基因在TRAMP肿瘤和TRAMP C1细胞系中通过启动子CpG超甲基化进行表观遗传调控;（7）CUR逆转了来自一组96个基因启动子的基因的甲基化状态，其中它们在人类PCa中已被报道过甲基化;（8）CUR逆转了已建立的癌症甲基化标记基因Neurog 1基因的表达，Neurog 1基因的去甲基化增加，同时Neurog 1 mRNA和蛋白质增加。尽管有这些有希望的结果，但是，我们对CUR/C.L.的表观遗传机制的理解存在重大差距。在疾病预防中，包括人PCa和CRC的癌症预防。根据我们初步研究的结果，我们假设C.L./ CUR治疗引起表观遗传修饰，导致PCa和CRC的预防，具有三个特定目的：（1）确定由姜黄（C.L.）（2）研究C.L. AOM/DSS诱导的CRC;（3）阐明C.L.在TRAMP C1、LNCaP和HT 29细胞培养系统中。

DESCRIPTION (provided by applicant): The products of root of Curcuma longa (C.L.), usually contain three major components, curcumin (CUR; ~77%), demethoxycurcumin (~17%) and bis-demethoxycurcumin (~3%), they are commonly used as botanical dietary supplements. The long term goal of this research project is to develop a safe and effective strategy to use C.L. in preventing diseases including prostate cancer (PCa) and colorectal cancer (CRC) in the US. PCa remains the most common malignancy in American men with an estimated 192,280 new cases and 27,360 deaths were expected in 2009, whereas CRC is the second most common cause of cancer death among men ages 40 to 79 years, and the third leading cause of cancer mortality in women with an estimated 53,439 new cases were diagnosed in 2010. Rationale for the studies proposed in this application is derived from our published as well as preliminary unpublished studies demonstrating that: (1) in PCa, CUR shows in vivo inhibition of prostate tumors in nude mice human PC-3 xenograft and TRAMP mice; (2) in CRC, CUR induces apoptosis in human HT-29 colon cancer cells and inhibits NFkB; an analog of CUR dibenzoylmethane, inhibits adenomas in APCmin mice, and CRC in AOM-DSS mice; (3) CUR regulate Nrf2-dependent genes in the intestine using Nrf2 KO mice; (4) As TRAMP mouse PCa progresses, there is a loss of the anti-oxidative stress transcription factor Nrf2 and Nrf2-target genes; (5) Feeding TRAMP mice with CUR resulted in re-expression of Nrf2 and Nrf2-target gene UGT1A1 in the TRAMP prostate tumor correlating with tumor suppression; (6) Nrf2 gene is epigenetically regulated in TRAMP tumor and TRAMP C1 cell line through promoter CpG hypermethylation; (7) CUR reverses the methylation status of genes from a panel of 96 gene promoters of which their hypermethylation has been reported in human PCa; (8) CUR reverses the expression of Neurog1 gene, an established cancer methylation marker gene, with increase in de-methylation of Neurog1 gene coupled with increase Neurog1 mRNA and protein. Despite these promising results, however, significant gaps exist in our understanding of the epigenetic mechanisms of CUR/C.L. in disease prevention including cancer prevention of human PCa and CRC. Based on the results of our preliminary studies we hypothesize that C.L./CUR treatment causes epigenetic modifications leading to prevention of PCa and CRC with three Specific Aims: (1) To determine the epigenetic alterations elicited by Curcuma Longa (C.L.) in prevention of prostate tumorigenesis in TRAMP mice; (2) To investigate the chemopreventive efficacy and epigenetic alterations of C.L. in AOM/DSS-induced CRC; and (3) To elucidate the in vitro epigenetic mechanisms of regulation of the genes obtained from in vivo Aims one and two by C.L. in TRAMP C1, LNCaP, and HT29 cell culture system.