Curcumin and Quercetin in Colon Cancer: Role of Macrophage-Induced Inflammation

姜黄素和槲皮素在结肠癌中：巨噬细胞诱导的炎症的作用

• 批准号: 7660641
• 负责人: ELIZABETH ANGELA MURPHY
• 金额: $ 19.01万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7660641
• 关键词: A Mouse; Address; Animals; Anorexia; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Behavior; Behavioral; Biological; CCL2 gene; Cachexia; Cancer Etiology; Cancer Patient; Carcinogenesis Mechanism; Cessation of life; Chronic; Circadian Rhythms; Classification; Colon Carcinoma; Colorectal Cancer; Consumption; Curcumin; Desire for food; Development; Diet; Etiology; Fatigue; Flavonoids; Genetically Engineered Mouse; Goals; Human; Individual; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-6; Intervention; Investigation; Link; Malignant Neoplasms; Mediator of activation protein; Medical; Mus; Neoplasm Metastasis; PTGS2 gene; Pathway interactions; Pharmaceutical Preparations; Physical activity; Placebos; Play; Polyps; Population; Prevention; Process; Property; Public Health; Quality of life; Quercetin; Risk Factors; Role; Safety; Spices; Staging; Techniques; Testing; Tissues; Transgenic Model; Treatment Protocols; Tumor Promotion; United States; angiogenesis; cancer diagnosis; cancer prevention; cancer risk; carcinogenesis; colorectal cancer prevention; dietary constituent; dietary supplements; fruits and vegetables; macrophage; metaplastic cell transformation; mouse model; non-genetic; nutrition; overexpression; prevent; public health relevance; response; stem; therapeutic target; tumor; tumor progression; tumorigenesis; wasting

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second leading cause of cancer death in the United States and the fourth most commonly diagnosed cancer. There is increasing recognition of diet-induced modulation of inflammatory responses as being central to the processes of human carcinogenesis. The argument for this stems from the observations that pro-inflammatory states are closely linked to tumor promotion. The consumption of the anti- inflammatory dietary constituents curcumin, which is a component of the Indian spice currie, and quercetin, a flavonoid present in various fruits and vegetables, have been associated with reduced CRC risk. Such components of diet are generally known to have a much wider safety margin with chronic use than are anti- inflammatory drugs, which make them more viable candidates to aid in cancer prevention. While a number of studies have examined the effects of dietary supplements on inflammation in cancer, none have specifically examined the role of tissue macrophages (Ms), primary mediators of inflammation, on these effects. Further, few have examined combinations of dietary supplements on the biological mechanisms of carcinogenesis. The overarching goal of this proposed project is to 1) determine the independent and combined effects of the anti-inflammatory dietary constituents curcumin and quercetin on CRC progression, and 2) to determine whether these benefits result from a reduction in M-induced inflammation. It is clear that M-induced inflammation plays an important part in the initiation and progression of CRC, and it may also be responsible for various sickness behaviors like fatigue, lack of appetite, and body wasting that can drastically decrease quality of life in CRC patients. A substantial proportion and perhaps the majority of CRCs are associated with non-genetic factors, such as inadequate and/or over nutrition, which can amplify inflammation in a number of ways. An independent, additive or synergistic effect of the anti-inflammatory dietary constituents curcumin and quercetin may be of critical public health significance in the prevention of CRC. The specific aims of this project are to 1) to elucidate the combined effects of curcumin and quercetin on M infiltration, inflammation, CRC progression and host survival and 2) to more specifically determine the role of M-induced inflammation on these effects. A mouse transgenic model of CRC will be used to determine the independent and combined effects of curcumin and quercetin on inflammatory processes, M infiltration, tumor progression and host survival at specific stages of CRC (e.g. prevention versus treatment). Furthermore, we will use M manipulation techniques to evaluate whether Ms are an important common pathway of the effects of curcumin and quercetin on inflammation, tumor progression and host survival. The overall goal of this project is to develop a clinically testable regimen to delay and/or prevent CRC and to begin to understand if the mechanisms of the effects are related to M infiltration and subsequent inflammation that could be targeted by further behavioral and or medical treatment. PUBLIC HEALTH RELEVANCE: The dietary compounds curcumin, a component of the Indian spice curry, and quercetin, a component of some fruits and vegetables, have anti-inflammatory properties and have been associated with reduced colon cancer risk. These compounds modify inflammatory processes which may be linked with the formation and development of tumors. The goal of the proposed study is to investigate the independent and combined effects of curcumin and quercetin on the progression of colon cancer and to determine if these effects result from a reduction in macrophage-induced inflammation.

描述（由申请人提供）：结直肠癌（CRC）是美国癌症死亡的第二大原因，也是第四大最常见的诊断癌症。越来越多的人认识到饮食诱导的炎症反应调节是人类致癌过程的核心。这一论点源于促炎状态与肿瘤促进密切相关的观察结果。食用抗炎膳食成分姜黄素（印度香料咖喱的一种成分）和槲皮素（各种水果和蔬菜中存在的一种黄酮类化合物）与降低CRC风险有关。众所周知，这些饮食成分在长期使用时比抗炎药物具有更大的安全范围，这使得它们更有可能帮助预防癌症。虽然许多研究已经检查了膳食补充剂对癌症炎症的影响，但没有一项研究专门检查了组织巨噬细胞（Ms），炎症的主要介质对这些影响的作用。此外，很少有人研究膳食补充剂的组合对致癌的生物学机制。该项目的总体目标是：1）确定抗炎饮食成分姜黄素和槲皮素对CRC进展的独立和联合作用，2）确定这些益处是否来自M诱导的炎症减少。很明显，M诱导的炎症在CRC的发生和进展中起着重要作用，它也可能导致各种疾病行为，如疲劳，食欲不振和身体消瘦，这些行为可能会大大降低CRC患者的生活质量。很大一部分，也许是大多数CRC与非遗传因素有关，例如营养不足和/或过度营养，这可以以多种方式放大炎症。抗炎饮食成分姜黄素和槲皮素的独立、相加或协同作用可能对预防CRC具有重要的公共卫生意义。该项目的具体目的是1）阐明姜黄素和槲皮素对M浸润、炎症、CRC进展和宿主存活的联合作用，2）更具体地确定M诱导的炎症对这些作用的作用。将使用CRC的小鼠转基因模型来确定姜黄素和槲皮素对CRC特定阶段的炎症过程、M浸润、肿瘤进展和宿主存活的独立和组合作用（例如预防与治疗）。此外，我们将使用M操作技术来评估MS是否是姜黄素和槲皮素对炎症，肿瘤进展和宿主存活的影响的重要共同途径。该项目的总体目标是开发一种临床可测试的方案，以延迟和/或预防CRC，并开始了解影响机制是否与M浸润和随后的炎症相关，这些炎症可以通过进一步的行为和/或药物治疗来靶向。公共卫生相关性：饮食化合物姜黄素，印度香料咖喱的一种成分，槲皮素，一些水果和蔬菜的一种成分，具有抗炎特性，并与降低结肠癌风险有关。这些化合物改变可能与肿瘤的形成和发展有关的炎症过程。这项研究的目的是研究姜黄素和槲皮素对结肠癌进展的独立和联合作用，并确定这些作用是否是由于巨噬细胞诱导的炎症减少。