Synergistic anticancer effects of docosahexanoic acid and curcumin

二十二碳六烯酸和姜黄素的协同抗癌作用

• 批准号: 7752876
• 负责人: Rafat Ali Siddiqui
• 金额: $ 6.75万
• 依托单位: INDIANA UNIVERSITY HEALTH, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-08 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7752876
• 关键词: Acids; Apoptosis; Apoptotic; Applications Grants; Asia; Biological Availability; Breast Cancer Cell; Breast Cancer Model; Cancer Model; Cancer Patient; Cancer cell line; Carcinogens; Cell Line; Ceramides; Combined Modality Therapy; Curcumin; Data; Development; Diet; Dietary Component; Docosahexaenoic Acids; Dose; Estrogen Receptor 2; Fathers; Fatty Acids; Fishes; Folk Medicine; Food; Future; Goals; Health Benefit; Human; Individual; Investigation; Japan; Knowledge; Laboratories; Lead; Malignant Neoplasms; Mediating; Mediator of activation protein; Medicine; Molecular; Nutrient; Nutritional; Omega-3 Fatty Acids; Outcome; Outcome Study; PPAR gamma; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Prevention; Preventive; Public Health; Recommendation; Recurrence; Research; Research Project Grants; Role; Signal Pathway; State Medicine; TP53 gene; Testing; Therapeutic Agents; Therapeutic Effect; Tissues; Tumeric; Water; Work; Xenograft Model; Xenograft procedure; base; cancer initiation; chemotherapy; effective therapy; experience; high risk; improved; innovation; malignant breast neoplasm; oncoprotein p21; p53 Signaling Pathway; polyphenol; prevent; synergism; tumor; tumor progression

DESCRIPTION (provided by applicant): It is becoming apparent that the major obstacles to the successful use of individual nutritional compounds as preventive or therapeutic agents are their efficacy and bioavailability. Traditionally, nutritional compounds in "folk medicine" are used in an unmodified form, as concentrated extracts. Given the fact that the human diet consists of multiple nutrients, it is likely that nutrients in the diet act synergistically to provide health benefits. The concept that food components act in synergism is not new. Centuries ago Hippocrates, the father of medicine, stated "Let food be thy medicine, and let thy medicine be food." Based on this rationale we propose to investigate the synergistic effects of two dietary components: docosahexaenoic acid (DHA) and curcumin (CCM). Our recent studies demonstrate that DHA induced apoptosis in breast cancer cells via enhanced expression of a key cell cycle regulator, p21. Data from other laboratories indicate that CCM also induces p21 expression. Expression of p21 is regulated upstream through multiple mechanisms, including ceramide, peroxisome proliferator-activated receptor-gamma (PPAR?), and p53-mediated pathways. It is apparent that these mediators can be regulated by DHA and/or CCM through common and divergent pathways that may cause a synergistic effect on p21 expression. Our central hypothesis is that DHA and CCM initiate common and divergent cellular pathways that synergistically induce apoptosis by regulating p21 expression. We will test our hypothesis using two specific aims: Specific Aim 1: Determine the synergistic effect of DHA and CCM on breast cancer cells. We will test combinations of DHA and CCM to characterize their apoptotic effects in different breast cancer cell lines. We will investigate common (ceramide formation) and divergent (PPAR? and p53 activation/expression) pathways for their synergistic effects on p21 expression. Specific Aim 2: Determine the preventive/therapeutic effects of DHA and CCM in a breast cancer model. We anticipate that combined treatment with DHA and CCM will be more effective than treatment with DHA or CCM alone in preventing breast cancer development. We will use breast cancer xenograft and carcinogen-induced breast cancer models to further confirm the common (ceramide) and divergent (PPAR? and/or p53) signaling pathways on the synergistic induction of p21 expression by DHA and CCM. The proposed investigation is innovative because the synergy of DHA and CCM has never been studied in any cancer model. Our studies are significant because the study outcome will lead to further investigation to determine whether combinations of nutrients provide synergistic effects to prevent breast cancer to those at a high risk of developing cancer as well as to prevent the recurrence or spread to other tissues after initial chemotherapy. We anticipate that the results of this study will help us develop an expanded research project for a future R01 grant application. Based on these studies, we will propose studies on different cancer models for the prevention, treatment, and reoccurrence of tumors using combinations of other nutritional compounds.

描述（由申请人提供）： 越来越明显的是，成功使用单个营养化合物作为预防或治疗剂的主要障碍是它们的功效和生物利用度。传统上，“民间药物”中的营养化合物以未经修饰的形式用作浓缩提取物。鉴于人类饮食由多种营养素组成，饮食中的营养素很可能协同作用以提供健康益处。食物成分协同作用的概念并不新鲜。几个世纪前，医学之父希波克拉底曾说过：“让食物成为你的药物，让你的药物成为食物。”基于这一原理，我们建议研究两种膳食成分的协同效应：二十二碳六烯酸（DHA）和姜黄素（CCM）。我们最近的研究表明，DHA 通过增强关键细胞周期调节因子 p21 的表达来诱导乳腺癌细胞凋亡。其他实验室的数据表明 CCM 也诱导 p21 表达。 p21 的表达通过多种机制受到上游调节，包括神经酰胺、过氧化物酶体增殖物激活受体-γ (PPAR?) 和 p53 介导的途径。显然，这些介质可以通过共同和不同的途径受到 DHA 和/或 CCM 的调节，这可能会对 p21 表达产生协同效应。我们的中心假设是 DHA 和 CCM 启动共同和不同的细胞途径，通过调节 p21 表达协同诱导细胞凋亡。我们将使用两个具体目标来检验我们的假设： 具体目标 1：确定 DHA 和 CCM 对乳腺癌细胞的协同作用。我们将测试 DHA 和 CCM 的组合，以表征它们在不同乳腺癌细胞系中的细胞凋亡作用。我们将研究共同（神经酰胺形成）和不同（PPAR？和 p53 激活/表达）途径对 p21 表达的协同作用。具体目标 2：确定 DHA 和 CCM 在乳腺癌模型中的预防/治疗效果。我们预计，在预防乳腺癌方面，DHA 和 CCM 联合治疗将比单独使用 DHA 或 CCM 治疗更有效。我们将使用乳腺癌异种移植和致癌物诱导的乳腺癌模型来进一步确认DHA和CCM协同诱导p21表达的共同（神经酰胺）和分歧（PPAR？和/或p53）信号通路。这项研究具有创新性，因为 DHA 和 CCM 的协同作用从未在任何癌症模型中进行过研究。我们的研究意义重大，因为研究结果将导致进一步研究，以确定营养素组合是否能提供协同效应，以预防癌症高危人群患乳腺癌，并防止初次​​化疗后复发或扩散到其他组织。我们预计这项研究的结果将帮助我们为未来的 R01 拨款申请开发一个扩展的研究项目。基于这些研究，我们将提出对不同癌症模型的研究，以使用其他营养化合物的组合来预防、治疗和复发肿瘤。