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: 8913687
• 负责人: Ah-Ng Tony Kong
• 金额: $ 44.99万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8913687
• 关键词: Age; American; 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 Carcinoma; Colorectal Cancer; Coupled; Curcumin; DNA Methyltransferase Inhibitor; Deoxycytidine; Diagnosis; Disease; Effectiveness; 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; PC3 cell line; Phase; Plant Roots; Prevention; Prostatic Neoplasms; Proteins; Publishing; Regimen; Reporting; Research Project Grants; Signal Pathway; Site; Sodium Dextran Sulfate; Therapeutic; Trichostatin A; Tumeric; Tumor Suppression; UGT1A1 gene; Woman; Xenograft procedure; adenoma; aged; analog; antioxidant enzyme; base; cancer cell; cancer chemoprevention; cancer prevention; colon tumorigenesis; cost effective; demethoxycurcumin; design; dibenzoylmethane; dietary supplements; disorder prevention; feeding; human FRAP1 protein; in vivo; men; methylation biomarker; mortality; mouse model; neoplastic cell; prevent; promoter; prostate cancer prevention; prostate carcinogenesis; success; transcription factor; transgenic adenocarcinoma of mouse prostate; tumor

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.

描述（申请人提供）：姜黄根（C.L.）的产品，通常含有姜黄素（CUR；~77%）、去甲氧基姜黄素（~17%）和双去甲氧基姜黄素（~3%）三种主要成分，它们通常用作植物膳食补充剂。该研究项目的长期目标是开发一种安全有效的策略来使用 C.L.在美国预防前列腺癌 (PCa) 和结直肠癌 (CRC) 等疾病。 PCa 仍然是美国男性中最常见的恶性肿瘤，2009 年估计有 192,280 例新病例，预计有 27,360 例死亡，而 CRC 是 40 至 79 岁男性中第二大最常见的癌症死亡原因，也是癌症死亡的第三大原因2010 年估计有 53,439 例新病例被诊断为女性。本申请中提出的研究的基本原理源自我们已发表的以及初步的未发表的研究表明：（1）在 PCa 中，CUR 在裸鼠、人 PC-3 异种移植物和 TRAMP 小鼠体内显示出对前列腺肿瘤的抑制作用； (2)在CRC中，CUR诱导人HT-29结肠癌细胞凋亡并抑制NFkB； CUR 二苯甲酰甲烷的类似物，可抑制 APCmin 小鼠的腺瘤和 AOM-DSS 小鼠的 CRC； (3)利用Nrf2 KO小鼠，CUR调节肠道中Nrf2依赖性基因； (4)随着TRAMP小鼠PCa的进展，抗氧化应激转录因子Nrf2和Nrf2靶基因丢失； (5)用CUR喂养TRAMP小鼠导致TRAMP前列腺肿瘤中Nrf2和Nrf2靶基因UGT1A1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高甲基化受到表观遗传调控； (7) CUR 逆转了一组 96 个基因启动子的基因甲基化状态，这些启动子在人类 PCa 中已被报道过甲基化； (8) CUR 逆转 Neurog1 基因（一种已确定的癌症甲基化标记基因）的表达，增加了 Neurog1 基因的去甲基化，同时增加了 Neurog1 mRNA 和蛋白质。然而，尽管取得了这些令人鼓舞的结果，但我们对 CUR/C.L 表观遗传机制的理解仍存在重大差距。疾病预防，包括人类前列腺癌和结直肠癌的癌症预防。根据我们的初步研究结果，我们假设 C.L./CUR 治疗会引起表观遗传修饰，从而预防前列腺癌和结直肠癌，其具体目标有以下三个：(1) 确定姜黄 (C.L.) 在预防前列腺肿瘤发生中引起的表观遗传改变在 TRAMP 小鼠中； (2) 探讨C.L.的化学预防功效和表观遗传改变。在 AOM/DSS 诱发的 CRC 中； (3) 阐明 C.L. 从体内目标一和目标二获得的基因的体外表观遗传调控机制。 TRAMP C1、LNCaP 和 HT29 细胞培养系统中。