Soy sphingadienes and related compounds in colon cancer chemoprevention and treat

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，它们涉及致癌、肿瘤进展和获得耐药性的各个方面。与正常肠组织相比，鞘脂代谢基因在肠肿瘤中异常表达，从而促进肿瘤进展。此外，饮食中的鞘脂，如豆制品中发现的鞘脂，通过促进肠上皮细胞的更新，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sphingadienes的生长调节鞘脂家族，该家族天然存在于果蝇中，并且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，这是癌症中的关键信号中枢。我们的初步研究结果还表明，鞘氨醇抑制2-catenin/Wnt信号通路参与结肠癌的发生。最后，鞘氨醇二烯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测试膳食鞘氨二烯和相关鞘氨二烯化合物是预防和/或治疗结肠癌的安全有效的药剂的假设，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）表征鞘氨醇二烯对结肠上皮细胞和结肠癌细胞的作用; 2）确定鞘氨醇二烯在小鼠中的代谢和毒性特征; 3）确定鞘氨醇二烯碱在体内预防肠道肿瘤发生和调节细胞信号传导途径的功效。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靶向癌症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，这些信息应有助于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的第二大常见癌症，也是癌症死亡的第三大原因。由于疾病的潜伏期长，从息肉发展到坦率的癌可能需要数年的时间，结肠癌是一种理想的疾病，采用化学预防策略。确定化学预防剂和饮食成分，促进肠上皮细胞的周转和阻止癌前病变的进展可能会对公众健康产生重大影响。该项目探讨了大豆和昆虫中发现的天然脂质家族的安全性，有效性和作用机制，这些脂质对结肠癌细胞具有细胞毒性，并在结肠癌的临床前模型中预防肿瘤。

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.