Soy sphingadienes and related compounds in colon cancer chemoprevention and treat

描述（由申请人提供）：鞘脂是一种保守的膜脂，可调节细胞增殖、凋亡和血管生成。因此，它们在致癌、肿瘤进展和获得耐药性的各个方面都有牵连。与正常肠道组织相比，鞘脂代谢基因在肠道肿瘤中表达异常，促进了肿瘤的进展。此外，饮食中的鞘脂，如豆制品中的鞘脂，通过促进肠上皮细胞的更新，降低了啮齿动物患结肠癌的风险。我们的实验室最近发现了一个生长调节鞘脂家族，叫做鞘脂烯，它天然存在于果蝇体内，结构上与大豆中的鞘脂烯相似。我们的初步研究表明，这些中链鞘脂烯对结肠癌细胞具有细胞毒性，因为它们能够抑制磷酸肌苷3激酶/AKT信号通路，这是癌症的一个关键信号枢纽。我们的初步研究结果还表明鞘脂素抑制与结肠癌发生有关的2-catenin/Wnt信号通路。最后，鞘脂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度表达的癌蛋白，是肠道肿瘤进展所必需的。这项应用的总体目标是验证膳食鞘脂烯和相关鞘脂烯化合物是安全有效的预防和/或治疗结肠癌的药物的假设，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)表征鞘脂素对结肠上皮细胞和结肠癌细胞的影响；2)测定鞘脂烯在小鼠体内的代谢和毒性；3)研究鞘脂烯碱基在体内预防肠道肿瘤发生和调节细胞信号通路中的作用。这些临床前研究应阐明鞘脂烯对结肠癌细胞发挥细胞毒性作用的分子机制，鞘脂烯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。他们将首次发现中链鞘脂烯和相关化合物在预防和/或治疗结肠癌方面的特殊潜力。它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。

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.