Curcuma Longa: epigenetic effects in prostate and colon cancer

姜黄：前列腺癌和结肠癌的表观遗传效应

• 批准号: 8234574
• 负责人: Ah-Ng Tony Kong
• 金额: $ 46.38万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8234574
• 关键词: Age; American; Antioxidants; Apoptosis; Apoptotic; Azoxymethane; Benchmarking; Binding; Biological Assay; Biological Markers; Botanicals; Cancer Etiology; Cell Culture System; Cell Death; Cell Line; Cell Proliferation; Cells; Cessation of life; Chemoprevention; Chemopreventive Agent; Chromatin; Clinical; Clinical Trials; Colon; Colon Carcinoma; Colorectal Cancer; Coupled; Curcuma longa; Curcumin; DNA Methyltransferase Inhibitor; Deoxycytidine; Diagnosis; Disease; Effectiveness; Enzymes; Epidermal Growth Factor Receptor; Epigenetic Process; Event; Future; Gene Expression Regulation; Gene Targeting; Genes; Goals; HT29 Cells; Histone Deacetylase Inhibitor; Histone H3; Human; Hypermethylation; In Vitro; Induction of Apoptosis; Intestines; LNCaP; Leukotriene B4; MAPK8 gene; Malignant Neoplasms; Malignant neoplasm of prostate; Messenger RNA; Methyl-CpG-Binding Protein 2; Methylation; Modification; Molecular; Mus; NQO1 gene; Nude Mice; Oxidative Stress; Phase; Plant Roots; Prevention; Prostate; Prostatic Neoplasms; Proteins; Publishing; Regimen; Reporting; Research Project Grants; Signal Pathway; Site; Sodium Dextran Sulfate; Therapeutic; Trichostatin A; Tumor Suppression; UGT1A1 gene; Woman; Xenograft procedure; adenoma; aged; analog; base; cancer cell; cancer chemoprevention; cancer prevention; cost effective; demethoxycurcumin; design; dibenzoylmethane; dietary supplements; disorder prevention; feeding; human FRAP1 protein; in vivo; men; mortality; mouse model; neoplastic cell; prevent; promoter; prostate cancer prevention; success; transcription factor; tumor; tumorigenesis

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. PUBLIC HEALTH RELEVANCE: Curcuma longa (C.L.) is commonly used as a botanical dietary supplement. Better understanding of the molecular mechanism of C.L. via epigenetic alterations would enhance the use of C.L. in diseases prevention including prostate and colorectal cancers that would greatly benefits thousands of Americans.

描述（由申请人提供）：Curcuma Longa（C.L.）根的产物，通常包含三个主要成分，Curcumin（Cur; 〜77％），去甲氧基核蛋白（〜17％）和双甲氧西氧基核蛋白（〜3％），它们通常用作botanical Enitalial Enitalial饮食补充剂。该研究项目的长期目标是制定使用C.L.的安全有效策略。在美国预防包括前列腺癌（PCA）和大肠癌（CRC）在内的疾病。 PCA仍然是美国男性中最常见的恶性肿瘤，估计有192,280例新病例和27,360例死亡，而CRC是40至79岁的男性癌症死亡的第二大最常见原因，这是妇女癌症死亡率的第三个主要原因，估计有53,439例新病例的癌症死亡率是在2010年被诊断出来的。未发表的研究表明：（1）在PCA中，Cur显示了裸鼠人类PC-3异种移植物和流浪汉小鼠中前列腺肿瘤的体内抑制作用； （2）在CRC中，CUR诱导人HT-29结肠癌细胞的凋亡并抑制NFKB； Cur二苯甲酰甲烷的类似物，抑制APCMIN小鼠的腺瘤，而AOM-DSS小鼠中的CRC； （3）使用NRF2 KO小鼠调节肠中NRF2依赖基因； （4）随着流浪小鼠PCA的进展，抗氧化应激转录因子NRF2和NRF2靶基因的损失； （5）用cur喂养流浪汉小鼠导致在流浪汉前列腺肿瘤中重新表达NRF2和NRF2靶标基因UGT1A1与肿瘤抑制相关； （6）NRF2基因通过启动子CpG高甲基化在流浪汉肿瘤和流浪汉C1细胞系中表观遗传调节； （7）CUR CUR逆转基因的甲基化状态，从96个基因启动子中据报道，在人类PCA中报道了其高甲基化； （8）CUR逆转Neurog1基因（一种已建立的癌症甲基化标记基因）的表达，随着Neurog1基因的脱甲基化以及Neurog1 mRNA和蛋白质的增加，脱甲基化的表达。但是，尽管有这些有希望的结果，但我们对Cur/C.L的表观遗传机理的理解仍然存在明显的差距。预防疾病预防疾病，包括预防人PCA和CRC。基于我们的初步研究的结果，我们假设C.L./cur治疗会导致表观植物修饰，从而预防PCA和CRC的三个特定目的：（1）确定姜黄（C.L.）在预防tramp肿瘤中预防curcuma longa（C.L.）引起的表观遗传变化； （2）研究C.L.的化学预防功效和表观遗传改变。在AOM/DSS诱导的CRC中； （3）阐明了从体内获得的基因调节的体外表观遗传机制，其目标是C.L.在流浪汉C1中，LNCAP和HT29细胞培养系统。 公共卫生相关性：Curcuma Longa（C.L.）通常用作植物饮食补充剂。更好地了解C.L.的分子机制通过表观遗传改变将增强C.L.的使用。在预防疾病中，包括前列腺和结直肠癌，将大大受益于成千上万的美国人。