Targeting colorectal carcinogenesis using a cinnamon-derived food factor

描述(申请人提供)：结直肠癌(CRC)是全世界与肿瘤相关的发病率和死亡率的主要原因。最近的研究有力地表明，氧化还原敏感的转录因子Nrf2(核因子-E2相关因子2)是化学预防炎症诱导的结直肠癌发生的一个有前景的分子靶点。肉桂的研磨树皮通常被称为肉桂，是世界上消费最多的三种香料之一，然而食用肉桂对健康的影响大多还没有从分子水平上进行研究。最近，我们已经确定肉桂来源的食品因子肉桂醛是肉桂粉中的关键成分，负责在人类结肠细胞中有效地诱导Nrf2调节的抗氧化反应，赋予细胞保护，使其免受随后的氧化和遗传毒性伤害。我们建议进行探索性研究，以检验肉桂醛代表一种有效的化学预防饮食因素的假设，该因素通过调节Nrf2协调的细胞保护机制而针对结直肠癌的发生。为了验证这一假说，将追求以下特定目标：目标#1.确定在大肠上皮细胞中肉桂醛激活Nrf2的特定分子靶点。目的#2.在已被接受的小鼠模型中，测试以肉桂醛为基础的针对结直肠癌发生的干预的可行性，并确定Nrf2参与肉桂醛化学预防活性的机制。该项目的成功完成将产生关键的原则验证数据，指导未来临床前和临床研究的合理设计，这些研究旨在开发肉桂醛，用于针对人类结直肠癌发生的化学预防干预。

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is a major cause of tumor-related morbidity and mortality worldwide. Recent research strongly suggests that the redox-sensitive transcription factor Nrf2 (nuclear factor-E2-related factor 2) is a promising molecular target for chemoprevention of inflammation-driven colorectal carcinogenesis. The ground bark of Cinnamomum aromaticum (cassia) and Cinnamomum verum (Ceylon cinnamon), commonly referred to as 'cinnamon', is one of the three most consumed spices in the world, yet health effects of cinnamon consumption have remained mostly unexplored at the molecular level. Recently, we have identified the cinnamon-derived food factor cinnamaldehyde as the key principle in cinnamon powder responsible for potent induction of the Nrf2-regulated antioxidant response in human colon cells, conferring cytoprotection against subsequent oxidative and genotoxic insult. We propose exploratory research that tests the overall hypothesis that cinnamaldehyde represents a potent chemopreventive dietary factor targeting colorectal carcinogenesis through modulation of Nrf2-orchestrated cytoprotective mechanisms. To test this hypothesis, the following specific aims will be pursued: Aim #1. To define the specific molecular targets involved in Nrf2-activation by cinnamaldehyde in colorectal epithelial cells. Aim #2. To test feasibility of cinnamaldehyde-based intervention targeting colorectal carcinogenesis in an accepted murine model and to determine mechanistic involvement of Nrf2 in cinnamaldehyde chemopreventive activity. Successful completion of this project will generate critical proof-of-principle data guiding the rational design of future preclinical and clinical studies that aim at developing cinnamaldehyde for chemopreventive intervention targeting human colorectal carcinogenesis.