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

基本信息

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
项目类别：
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

项目摘要

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。因此，它们与癌发生、肿瘤进展和耐药性获得的各个方面有关。与正常肠道组织相比，鞘脂代谢基因在肠道肿瘤中异常表达，从而导致肿瘤进展。此外，饮食中的鞘脂（例如豆制品中的鞘脂）可促进肠上皮细胞的更新，从而降低啮齿动物患结肠癌的风险。我们的实验室最近发现了一个称为鞘氨醇的生长调节鞘脂家族，它天然存在于果蝇果蝇中，并且在结构上与大豆中发现的鞘氨醇相似。我们的初步研究表明，这些中链鞘氨醇对结肠癌细胞具有细胞毒性，因为它们能够抑制磷酸肌醇 3 激酶/AKT 信号通路（癌症中的关键信号中枢）。我们的初步研究结果还表明，鞘氨醇可抑制与结肠癌发生有关的 2-连环蛋白/Wnt 信号通路。最后，鞘氨醇具有抑制鞘氨醇激酶的潜力，鞘氨醇激酶是一种在结肠癌中过度表达的癌蛋白，是肠道肿瘤进展所必需的。本申请的总体目标是检验膳食二氢鞘氨醇和相关二氢鞘氨醇化合物是预防和/或治疗结肠癌的安全有效药物的假设，并阐明它们对结肠细胞施加影响的机制。为此，我们设计了三个具体目标：1）表征鞘氨脂对结肠上皮细胞和结肠癌细胞的影响； 2) 测定鞘氨醇在小鼠体内的代谢和毒性特征； 3) 确定鞘氨醇碱在体内预防肠道肿瘤发生和调节细胞信号通路的功效。这些临床前研究应阐明鞘氨醇对结肠癌细胞发挥细胞毒性作用的分子机制、鞘氨醇介导的细胞毒性的结构要求以及针对癌症中关键信号通路的能力。他们将是第一个解决中链鞘氨醇和相关化合物预防和/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，以促进最终转化为临床试验。公共卫生相关性：结肠癌是男性和女性第二大常见癌症，也是癌症死亡的第三大原因。由于这种疾病的潜伏期很长，从息肉发展成直肠癌可能需要数年时间，因此结肠癌是采用化学预防策略的理想疾病。识别促进肠上皮细胞更新并阻止癌前病变进展的化学预防剂和饮食成分可能会对公众健康产生重大影响。该项目探讨了在大豆和昆虫中发现的一系列天然脂质的安全性、有效性和作用机制，这些脂质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。