Truncated Inositol Glycans and Cancer

描述（由申请人提供）：拟议的工作将评估追求肌醇聚糖或类似物作为癌症治疗剂的潜力。初步研究表明，脂肪酰化肌醇聚糖（IG）选择性地杀死培养中的各种癌细胞类型，但对各种非癌细胞无害。假设这种IG通过刺激细胞有氧代谢起作用，从而逆转癌细胞中的瓦尔堡效应，并恢复这些细胞中的内在凋亡，但不损害正常细胞，因为它们已经在进行有氧代谢。拟议的工作有三个具体目标：目标1是开发一种改进的化学合成这种IG，允许简单的大规模制备，使其可以作为一种治疗剂在动物模型中的癌症进行评估。这将通过探索提高当前IG合成中关键合成步骤的选择性的方法来实现，以提供更高的产率并减少费力纯化的必要性。目的二是合成IG类似物，并评价其对转化细胞的细胞毒性的结构限制。将在酰基链、肌醇立体化学、连接的糖的数量和葡糖胺部分中进行各种修饰，并且将在针对培养的癌症和正常细胞系的体外细胞毒性测定中筛选所得化合物。目的3是验证肿瘤选择性IG细胞毒性是由于有氧代谢刺激引起的内源性凋亡的假设。这将通过确认细胞凋亡、评价代谢通量和检查信号传导途径中的中枢酶（如半胱天冬酶、PI-3 K、钙调磷酸酶、MEK、PARP和PPAR-gamma）的选择性抑制剂对IG细胞毒性的影响来进行测试。 这项工作与公共卫生高度相关，因为它既可以建立一类新的抗癌药物用于开发，也可以为其他尚未开发的抗癌药物提供新的靶点。

DESCRIPTION (provided by applicant): The proposed work will evaluate the potential for pursuing inositol glycans or analogues as therapeutic agents for cancer. Preliminary work has demonstrated that a fatty-acylated inositol glycan (IG) selectively kills a variety of cancer cell types in culture but is harmless to a variety of non-cancerous cells. The hypothesis is that this IG acts by stimulating cellular aerobic metabolism and thereby reverses the Warburg Effect in cancer cells and restores intrinsic apoptosis in these cells but does not harm normal cells because they are already performing aerobic metabolism. The proposed work has three specific aims: Aim 1 is to develop an improved chemical synthesis of this IG, permitting simple large-scale preparation so that it can be evaluated as a therapeutic agent in animal models of cancer. This will be achieved by exploring ways to improve the selectivity of key synthetic steps in the current IG synthesis to both afford higher yields and reduce the necessity of laborious purifications. Aim 2 is to synthesize IG analogues and evaluate the structural limitations for cytotoxicity toward transformed cells. Various modifications will be made in the acyl chain, the inositol stereochemistry, the number of attached sugars, and the glucosamine moiety, and the resulting compounds will be screened in an in vitro cytotoxicity assay against cultured cancer and normal cell lines. Aim 3 is to test the hypothesis that cancer-selective IG cytotoxicity is due intrinsic apoptosis caused by stimulation of aerobic metabolism. This will be tested by confirming apoptosis, evaluating metabolic flux, and examining the effect of selective inhibitors of central enzymes in signaling pathways (such as caspases, PI-3K, calcineurin, MEK, PARP, and PPAR-gamma) on IG cytotoxicity.. This work is highly relevant to public health because it may both establish a new class of anticancer agents for development and provide a new target for other yet to be developed anticancer agents.