Synergistic anticancer effects of docosahexanoic acid and curcumin

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，“民间医药”中的营养化合物以未经修饰的形式使用，如浓缩提取物。鉴于人类饮食由多种营养素组成的事实，饮食中的营养素可能协同作用以提供健康益处。食品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说：“让食物成为你的药物，让你的药物成为食物。“基于这一基本原理，我们建议研究两种饮食成分的协同作用：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的表达诱导乳腺癌细胞凋亡。来自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在上游调节，包括神经酰胺、过氧化物酶体增殖物激活受体-γ（PPAR？）、和p53介导的通路。很明显，这些介质可以通过共同和不同的途径由DHA和/或CCM调节，这可能对p21表达产生协同作用。我们的中心假设是，DHA和CCM启动共同的和不同的细胞途径，协同诱导细胞凋亡，通过调节p21的表达。我们将使用两个具体目标来测试我们的假设：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。我们将调查共同（神经酰胺形成）和分歧（过氧化物酶体增殖物激活受体？和p53活化/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/治疗作用。我们预计，在预防乳腺癌发展方面，DHA和CCM联合治疗将比单独使用DHA或CCM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，以进一步确认共同（神经酰胺）和分歧（过氧化物酶体增殖物激活受体？和/或p53）信号通路对DHA和CCM协同诱导p21表达的影响。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。我们的研究是重要的，因为研究结果将导致进一步的调查，以确定营养素的组合是否提供协同效应，以预防乳腺癌的高风险发展癌症，以及预防复发或扩散到其他组织后，初步化疗。我们预计，这项研究的结果将有助于我们开发一个扩大的研究项目，为未来的R 01赠款申请。基于这些研究，我们将提出使用其他营养化合物的组合来预防、治疗和复发肿瘤的不同癌症模型的研究。

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.