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.
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