The ceramide and sphingoid base backbones of sphingolipids are highly bioactive compounds that affect growth, differentiation, cell migration and apoptosis when added to transformed cells in culture. These findings have been shown to be relevant to cancer in vivo because addition of sphingolipids to the diets of CT1 mice that have been treated with a colon carcinogen (1,2-dimethylhydrazine) to Min mice (with a genetic defect in APC that predisposes them to cancer) reduces early indices of colon carcinogenesis (colonic cell proliferation and appearance of aberrant colonic crypt foci) as well as decreases the number of tumors. Based on the mechanisms of action of ceramides and sphingo bases (and structure- function relationships for the metabolism of these compounds), synthetic analogs have been prepared that are more potent that the naturally occurring compounds when tested against colon cancer cells in culture. This demonstrates the potential for sphingoid base analogs to be even more effective than ceramide and sphingosine against colon cancer cells. Thus, the goals of this grant are to develop libraries of novel sphingolipid analogs through directed combinatorial syntheses (as well as from selected natural sources), to conduct structure/function studies with these libraries with the goal of elucidating mechanism of action, and to conduct screens of the potency and selectivity of the analogs against in vitro and in vivo cancer models at Emory as well as at the NCI. The findings of these studies will identify the most effective compounds and strategies for use of sphingolipids for the prevention and treatment of colon cancer and, perhaps, other forms of neoplasia.
Showing the most recent 10 out of 11 publications
