Curcuma Longa: epigenetic effects in prostate and colon cancer

产品说明（申请人提供）：姜黄根（C.L.）的产品，通常含有三种主要成分：姜黄素（CUR; ~77%）、去甲氧基姜黄素（~17%）和双去甲氧基姜黄素（~3%），是常用的植物性膳食补充剂。本研究项目的长期目标是在美国开发一种安全有效的策略来使用c.l预防包括前列腺癌（PCa）和结直肠癌（CRC）在内的疾病。前列腺癌仍然是美国男性最常见的恶性肿瘤，2009年估计有192,280例新病例和27,360例死亡，而结直肠癌是40至79岁男性癌症死亡的第二大常见原因，也是女性癌症死亡的第三大原因，2010年估计有53,439例新诊断病例。本申请中提出的研究的基本原理来源于我们已发表的和初步未发表的研究，这些研究表明：(1)在PCa中，CUR对裸鼠、人PC-3异种移植和TRAMP小鼠的前列腺肿瘤有体内抑制作用；(2)在结直肠癌中，CUR诱导人HT-29结肠癌细胞凋亡并抑制NFkB；一种CUR二苯甲酰甲烷类似物，抑制APCmin小鼠的腺瘤和AOM-DSS小鼠的结直肠癌；(3) CUR通过Nrf2 KO小鼠调节肠道内Nrf2依赖基因；(4)随着TRAMP小鼠PCa的进展，抗氧化应激转录因子Nrf2和Nrf2靶基因的缺失；(5)用CUR喂养TRAMP小鼠，Nrf2和Nrf2靶基因UGT1A1在TRAMP前列腺肿瘤中重新表达，与肿瘤抑制相关；(6) Nrf2基因在TRAMP肿瘤和TRAMP C1细胞系中通过启动子CpG超甲基化受到表观遗传调控；(7) CUR逆转了一组96个基因启动子中基因的甲基化状态，这些基因的高甲基化已在人类PCa中被报道；(8) CUR逆转了已建立的癌症甲基化标记基因Neurog1基因的表达，Neurog1基因去甲基化的增加伴随着Neurog1 mRNA和蛋白的增加。然而，尽管有这些令人鼓舞的结果，我们对CUR/C.L.的表观遗传机制的理解仍存在显着差距预防疾病，包括预防人类前列腺癌和结直肠癌基于我们的初步研究结果，我们假设Curcuma Longa （Curcuma Longa， C.L.）治疗引起的表观遗传改变导致前列腺癌和结直肠癌的预防，有三个具体目的：(1)确定Curcuma Longa （C.L.）引起的表观遗传改变在预防TRAMP小鼠前列腺肿瘤发生中的作用；(2)探讨cl在AOM/ dss诱导的结直肠癌中的化学预防作用及表观遗传改变；(3)阐明c.l调控体内靶基因1和靶基因2在TRAMP C1、LNCaP和HT29细胞培养体系中的体外表观遗传机制。

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 Rationale for the studies proposed in this application is derived from our published as well as preliminary unpublished studies demonstrating that: (1) in PCa, CUR shows in vivo inhibition of prostate tumors in nude mice human PC-3 xenograft and TRAMP mice; (2) in CRC, CUR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.