Chemoprevention of Colorectal Cancer by Aldose Reductase Inhibition

描述（由申请人提供）： 慢性炎症性疾病和氧化应激是结直肠癌（CRC）的主要危险因素，CRC是癌症患者死亡的第二大原因。然而，氧化应激和炎症标志物增加导致CRC的机制尚不清楚。了解这些生化机制，特别是活性氧（ROS）在CRC病理生理学中的作用，将有助于开发更好的治疗策略。我们最近已经证明，醛糖还原酶（AR）是一种催化ROS诱导的脂质醛及其谷胱甘肽结合物（如HNE和GS-HNE至DHN和GS-DHN）还原的酶，是人结肠癌细胞中生长因子和精氨酸诱导的NF-：B活化的强制性介导剂。此外，我们已经表明，通过SiRNA的AR抑制或消融防止了培养物中以及裸鼠异种移植物中结肠癌细胞的生长。我们的长期目标是了解AR促进CRC进展的机制，并开发AR抑制剂（阿里斯）用于CRC的化学预防。 我们现在将系统地检验我们的假设，即ROS的作用部分是由AR介导的， 通过研究AR在培养细胞、裸鼠异种移植物和CRC小鼠模型中介导生长因子诱导的癌症生长中的作用，催化还原脂质过氧化物衍生的醛（LDAs）及其代谢物。我们的具体目标是1）研究AR抑制对生长因子诱导的培养人结肠癌细胞生长进展的影响，2）描述AR抑制/消融对裸鼠异种移植物中结肠癌进展的影响，以及3）描述AR抑制在小鼠模型中化学和遗传诱导的CRC中的化学预防功效。这些研究的完成应确定AR减少的LDA在介导致癌信号中的分子机制，并导致AR抑制剂作为CRC的优良化学预防药物的使用。健康 相关性：结肠癌是美国癌症患者死亡的第二大原因。我们的项目将确定结肠癌发生的机制，并最终导致新的化学预防方法的发展，以防止结肠癌死亡。

DESCRIPTION (provided by applicant): Chronic inflammatory diseases and oxidative stress are major risk factors of colorectal cancer (CRC), the second-ranked cause of death among cancer patients. However, the mechanisms through which increased oxidative stress and inflammatory markers cause CRC are not well understood. Understanding these biochemical mechanisms, especially the role of increased reactive oxygen species (ROS) in the pathophysiology of CRC, will help in developing better therapeutic strategies. We have recently demonstrated that aldose reductase (AR) an enzyme that we have shown catalyzes the reduction of ROS-induced lipid aldehydes and their glutathione-conjugates (such as HNE and GS-HNE to DHN and GS-DHN),is an obligatory mediator of growth factor and cytokine-induced NF-:B activation in human colon cancer cells. Further, we have shown that AR inhibition or ablation by SiRNA prevents the growth of colon cancer cells in culture as well as in nude mice xenografts. Our long term goal is to understand the mechanisms by which AR contributes to CRC progression, and to develop AR inhibitors (ARIs) for chemoprevention of CRC. We will now systematically examine our hypothesis that the effects of ROS are in part mediated by AR- catalyzed reduced lipid peroxidation-derived aldehydes (LDAs) and their metabolites by investigating the role of AR in mediating growth factor-induced cancer growth in cultured cells, nude mice xenografts and murine models of CRC. Our specific aims are 1) Investigate the effects of AR inhibition on the growth factor-induced progression of cultured human colon cancer cell growth, 2) Delineate the effects of AR inhibition/ablation on colon cancer progression in nude mouse xenografts, and 3) Delineate the chemopreventive efficacy of AR inhibition in chemically and genetically-induced CRC in murine models. Completion of these studies should identify the molecular mechanisms of AR- reduced LDAs in mediating carcinogenic signals, and lead to use of AR inhibitors as excellent chemopreventive drugs for CRC.HEALTH Relevance: colon cancer is the second leading cause of death among the cancer patients in US. Our project will determine the mechanisms of colon carcinogenesis, and ultimately lead to the development of new chemopreventive approaches to prevent death from colon cancer.