Soy sphingadienes and related compounds in colon cancer chemoprevention and treat

大豆鞘氨醇及相关化合物在结肠癌的化学预防和治疗中的作用

• 批准号: 7916337
• 负责人: JULIE D SABA
• 金额: $ 19.8万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7916337
• 关键词: AKT Signaling Pathway; Address; Animals; Apoptosis; Apoptotic; Autopsy; Biochemical; Biological Assay; Blood; Brush Border; C57BL/6 Mouse; CD31 Antigens; Cancer Etiology; Carcinoma; Cell Death; Cell Fractionation; Cell Line; Cell Proliferation; Cells; Ceramides; Chemistry; Chemopreventive Agent; Clinical Trials; Colon; Colon Carcinoma; Data; Diet; Disease; Dose; Drosophila genus; Drug resistance; Enzymes; Epithelial; Epithelial Cells; Euthanasia; Exhibits; Family; Freezing; Genes; Glucosylceramides; Goals; Growth; Hematology; High Pressure Liquid Chromatography; Human; Immunoblotting; Immunofluorescence Immunologic; Insecta; Intestinal Mucosa; Intestinal Neoplasms; Intestinal Polyposis; Intestinal Polyps; Intestines; Laboratories; Lesion; Lipids; Location; Malignant - descriptor; Malignant Neoplasms; Mass Spectrum Analysis; Maximum Tolerated Dose; Mediating; Membrane Lipids; Metabolism; Microscopic; Molecular; Mus; NMR Spectroscopy; Nature; Non-Malignant; Oncogene Proteins; PTEN gene; Phosphatidylinositols; Phosphotransferases; Plants; Polyps; Pre-Clinical Model; Prevention; Proto-Oncogene Proteins c-akt; Public Health; Research; Resolution; Risk; Rodent; Safety; Serum; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Solubility; Sphingolipids; Surveys; Testing; Time; Tissues; Toxic effect; Transfection; Translations; Vertebral column; Woman; adenoma; angiogenesis; base; cancer cell; cancer chemoprevention; carcinogenesis; cell growth; cohort; colon carcinogenesis; cytotoxic; cytotoxicity; dietary constituent; enzyme activity; feeding; fungus; human disease; in vivo; inhibitor/antagonist; intestinal epithelium; liver function; male; men; mortality; mouse model; novel; overexpression; preclinical study; prevent; public health relevance; soy; sphingosine kinase; tumor; tumor progression; tumorigenesis; uptake

DESCRIPTION (provided by applicant): Sphingolipids are conserved membrane lipids that regulate cell proliferation, apoptosis and angiogenesis. As such, they have been implicated in various aspects of carcinogenesis, tumor progression and the acquisition of drug resistance. Genes of sphingolipid metabolism are aberrantly expressed in intestinal tumors compared to normal intestinal tissue, contributing to tumor progression. In addition, dietary sphingolipids such as those found in soy products reduce the risk of colon cancer in rodents by facilitating turnover of intestinal epithelial cells. Our laboratory recently identified a family of growth-regulating sphingolipids called sphingadienes that occur naturally in the fruitfly Drosophila and are structurally similar to sphingadienes found in soy. Our preliminary studies demonstrate that these medium-chain sphingadienes are cytotoxic to colon cancer cells by virtue of their ability to inhibit the phosphoinositide 3 kinase/AKT signaling pathway, a critical signaling hub in cancer. Our preliminary findings also indicate that sphingadienes inhibit the 2-catenin/Wnt signaling pathway implicated in colon carcinogenesis. Finally, sphingadienes have the potential to inhibit sphingosine kinase, an oncoprotein that is overexpressed in colon cancer and required for intestinal tumor progression. The overall goal of this application is to test the hypothesis that dietary sphingadienes and related sphingadiene compounds are safe and effective agents to prevent and/or treat colon cancer and to elucidate the mechanisms by which they exert their influence on colonic cells. Toward that end, we have devised three Specific Aims: 1) To characterize the effects of sphingadienes on colonic epithelial and colon cancer cells; 2) To determine the metabolism and toxicity profile of sphingadienes in mice; 3) To establish the efficacy of sphingadiene bases in preventing intestinal tumorigenesis and regulating cell signaling pathways in vivo. These preclinical studies should elucidate the molecular mechanisms by which sphingadienes exert their cytotoxic effects on colon cancer cells, the structural requirements for sphingadiene-mediated cytotoxicity and the ability to target key signaling pathways in cancer. They will be the first to address the specific potential of medium-chain sphingadienes and related compounds to prevent and/or treat colon cancer. They will also provide information regarding efficacy, metabolism and toxicity that should facilitate eventual translation into clinical trials. PUBLIC HEALTH RELEVANCE: Colon cancer is the second most common cancer of men and women and the third leading cause of cancer mortality. Because of the long latency of the disease, which develops from polyps that may take years to progress to frank carcinoma, colon cancer is an ideal disease for which to employ chemopreventive strategies. Identifying chemopreventive agents and dietary constituents that facilitate the turnover of intestinal epithelial cells and block the progression of preneoplastic lesions could have a significant impact on public health. This project explores the safety, efficacy and mechanism of action of a family of natural lipids found in soy and insects that exhibit cytotoxicity against colon cancer cells and prevent tumors in a preclinical model of colon cancer.

描述（由申请人提供）：鞘脂是调节细胞增殖，凋亡和血管生成的保守膜脂质。因此，它们与癌变，肿瘤进展和耐药性的获取有关。与正常肠道组织相比，在肠道肿瘤中，鞘脂代谢的基因异常表达，导致肿瘤进展。此外，通过促进肠上皮细胞的周转，饮食中的鞘脂（例如大豆产品中发现的鞘脂）降低了啮齿动物的结肠癌风险。我们的实验室最近确定了一个自然发生在果蝇果蝇中的鞘脂的生长调节鞘脂的家族，在结构上与大豆中发现的Sphingadienes相似。我们的初步研究表明，这些中链鞘脂二烯由于能够抑制磷酸肌醇3激酶/AKT信号通路的能力而对结肠癌细胞具有细胞毒性，这是癌症中的关键信号中心。我们的初步发现还表明，辛加二烯抑制了与结肠致癌作用有关的2-catenin/wnt信号传导途径。最后，鞘胺有可能抑制鞘氨醇激酶，鞘氨酸激酶是一种在结肠癌中过表达的癌蛋白，肠道肿瘤进展所必需的。该应用的总体目的是检验以下假设：饮食中的辛加二烯和相关的鞘胺化合物是预防和/或治疗结肠癌并阐明它们对结肠细胞影响的机制的安全有效的药物。为此，我们设计了三个特定的目标：1）表征辛加二烯对结肠上皮和结肠癌细胞的影响； 2）确定小鼠鞘胺的代谢和毒性特征； 3）建立鞘烯丙烯碱在预防肠道肿瘤发生和调节体内细胞信号通路方面的功效。这些临床前研究应阐明鞘胺对结肠癌细胞的细胞毒性作用，鞘磷脂介导的细胞毒性的结构要求以及靶向癌症中关键信号途径的能力。他们将是第一个解决中链鞘胺和相关化合物以预防和/或治疗结肠癌的特定潜力的人。他们还将提供有关功效，代谢和毒性的信息，这些信息应促进最终转化为临床试验。 公共卫生相关性：结肠癌是第二大常见的男性和女性癌症，也是癌症死亡率的第三主要原因。由于这种疾病的潜伏期很长，这种疾病是由息肉发展而来的，可能需要数年才能发展到弗兰克癌，因此结肠癌是一种采用化学预防策略的理想疾病。鉴定促进肠上皮细胞营业额并阻止前肿瘤病变进展的化学预防剂和饮食成分可能会对公共卫生产生重大影响。该项目探讨了在大豆和昆虫中发现的一系列天然脂质家族的安全性，功效和机制，这些脂质和昆虫对结肠癌细胞表现出细胞毒性，并在结肠癌的临床前模型中预防肿瘤。