Truncated Inositol Glycans and Cancer

描述(由申请人提供)：拟议的工作将评估寻求肌醇多聚糖或类似物作为癌症治疗剂的潜力。初步研究表明，脂肪酰化的肌醇多聚糖(IG)选择性地杀死培养中的各种类型的癌细胞，但对各种非癌细胞无害。假说是，这种免疫球蛋白通过刺激细胞有氧代谢发挥作用，从而逆转癌细胞的华宝效应，恢复这些细胞的内在凋亡，但不会损害正常细胞，因为它们已经在进行有氧代谢。这项拟议的工作有三个具体目标：目标1是开发一种改进的这种IG的化学合成方法，允许简单、大规模的制备，以便能够在癌症动物模型中评估其作为治疗剂的作用。这将通过探索提高当前IG合成中关键合成步骤的选择性来实现，从而既提供更高的产率，又减少费力提纯的必要性。目的2是合成免疫球蛋白类似物，并评价其对转化细胞的细胞毒性的结构限制。将在酰链、肌醇立体化学、结合糖的数量和氨基葡萄糖部分进行各种修饰，并在体外对培养的癌症和正常细胞系进行细胞毒性试验。目的3验证肿瘤选择性免疫球蛋白细胞毒性是由有氧代谢刺激引起的内源性细胞凋亡的假设。这将通过确认细胞凋亡，评估代谢通量，以及检测信号通路中中央酶的选择性抑制剂(如caspase、PI-3K、Calcineurin、MEK、PARP和PPAR-Gamma)对IG细胞毒性的影响来检验。 这项工作与公众健康高度相关，因为它既可能建立一类新的抗癌药物进行开发，也可能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.