Targeting colorectal carcinogenesis using a cinnamon-derived food factor

描述（由申请人提供）：结直肠癌（CRC）是全球肿瘤相关发病率和死亡率的主要原因。最近的研究强烈表明，氧化还原敏感性转录因子Nrf2（核因子E2相关因子2）是一个有前途的分子靶点，用于炎症驱动的结直肠癌的化学预防。肉桂（Cinnamomum aromaticum）和锡兰肉桂（Cinnamomum verum）的地面树皮，通常被称为“肉桂”，是世界上三种消费量最大的香料之一，但肉桂消费对健康的影响在分子水平上仍未被探索。最近，我们已经确定了肉桂衍生的食物因子肉桂醛的关键原则，肉桂粉负责有效诱导Nrf2调节的抗氧化反应在人类结肠细胞，赋予细胞保护，防止随后的氧化和遗传毒性的侮辱。我们提出了探索性研究，测试的总体假设，肉桂醛是一种有效的化学预防饮食因子，通过调节Nrf2协调的细胞保护机制，靶向结直肠癌的发生。为了检验这一假设，将追求以下具体目标：目标1。明确肉桂醛激活结直肠上皮细胞Nrf2的特异性分子靶点。目标2。在公认的小鼠模型中测试以肉桂醛为基础的干预靶向结直肠癌发生的可行性，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理验证数据，指导未来临床前和临床研究的合理设计，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.