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，是癌症患者的第二大死亡原因。然而，氧化应激和炎症标志物增加导致结直肠癌的机制尚不清楚。了解这些生化机制，特别是活性氧（ROS）在结直肠癌病理生理中的作用，将有助于制定更好的治疗策略。我们最近已经证明醛糖还原酶（AR）是一种酶，我们已经证明它可以催化ros诱导的脂质醛及其谷胱甘肽偶联物（如HNE和GS-HNE到DHN和GS-DHN）的还原，是生长因子和细胞因子诱导的人结肠癌细胞中NF-:B活化的强制性介质。此外，我们已经证明，通过SiRNA抑制或消融AR可以阻止培养和裸鼠异种移植结肠癌细胞的生长。我们的长期目标是了解AR促进结直肠癌进展的机制，并开发用于结直肠癌化学预防的AR抑制剂（ARIs）。现在，我们将通过研究AR在培养细胞、裸鼠异种移植和小鼠CRC模型中介导生长因子诱导的癌症生长中的作用，系统地检验我们的假设，即ROS的作用部分是由AR催化的脂质过氧化衍生醛（LDAs）及其代谢物介导的。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结肠癌进展的影响；3)描述AR抑制对小鼠模型化学和遗传诱导的结直肠癌的化学预防作用。这些研究的完成将确定AR-还原LDAs介导致癌信号的分子机制，并导致AR抑制剂作为结直肠癌的优秀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.