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）： 显然，成功使用单个营养化合物作为预防剂或治疗剂的主要障碍是它们的功效和生物利用度。传统上，“民间医学”中的营养化合物以未修饰的形式使用，作为集中提取物。鉴于人类饮食由多种营养素组成，因此饮食中的营养可能协同作用以提供健康益处。食品成分在协同作用中作用的概念并不是什么新鲜事。几个世纪前，医学之父希波克拉底（Hippocrates）说：“让食物成为你的药，让你的药成为食物。”基于此基本原理，我们建议研究两个饮食成分的协同作用：Docosahexaenoic Acid（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剂P21的表达诱导乳腺癌细胞的凋亡。来自其他实验室的数据表明，CCM还诱导P21表达。 p21的表达是通过多种机制在上游调节的，包括神经酰胺，过氧化物酶体增殖物激活的受体伽马（PPAR？）和p53介导的途径。显然，这些介体可以通过DHA和/或CCM通过常见和不同的途径来调节，这可能会对P21表达产生协同作用。我们的中心假设是DHA和CCM启动了常见和不同的细胞途径，通过调节P21表达来协同诱导凋亡。我们将使用两个特定目的检验我们的假设：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凋亡作用。我们将研究常见（神经酰胺形成）和分歧（PPAR？和p53激活/表达）途径，以使其对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/治疗作用。我们预计，与DHA和CCM的联合治疗将比仅使用DHA或CCM治疗在防止乳腺癌发展方面更有效。我们将使用乳腺癌异种移植物和致癌物诱导的乳腺癌模型，以进一步证实DHA和CCM对P21表达的协同诱导P21的共同（PPAR？和/或P53）信号通路。拟议的调查具有创新性，因为DHA和CCM的协同作用从未在任何癌症模型中得到研究。我们的研究很重要，因为该研究结果将导致进一步的研究，以确定营养的组合是否提供了协同作用，以防止患有高风险的乳腺癌以及在初始化学疗法后的复发或扩散到其他组织的乳腺癌。我们预计这项研究的结果将帮助我们为未来的R01赠款应用程序开发扩展的研究项目。基于这些研究，我们将使用其他营养化合物的组合对不同的癌症模型进行预防，治疗和再播肿瘤的研究。