Truncated Inositol Glycans and Cancer

描述（由申请人提供）：提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）在培养中选择性地杀死多种类型的癌细胞，但对多种非癌细胞无害。假设这种IG通过刺激细胞有氧代谢而起作用，从而逆转癌细胞中的Warburg效应并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，以便它可以作为癌症动物模型的治疗剂进行评估。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，以提供更高的收率并减少费力的纯化的必要性。目的2是合成IG类似物，并评估其结构限制对转化细胞的细胞毒性。将对酰基链、肌醇立体化学、附着糖的数量和氨基葡萄糖部分进行各种修饰，所得化合物将在体外细胞毒性试验中对培养的癌细胞和正常细胞系进行筛选。目的3是验证癌症选择性IG细胞毒性是由于有氧代谢刺激引起的内在凋亡的假设。这将通过确认细胞凋亡、评估代谢通量和检查信号通路中中心酶的选择性抑制剂（如半胱天冬酶、PI-3K、钙调磷酸酶、MEK、PARP和ppar - γ）对IG细胞毒性的影响来验证。

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.