Identification of metabolites with anticancer properties by computational metabolomics.

Certain endogenous metabolites can influence the rate of cancer cell growth. For example, diacylglycerol, ceramides and sphingosine, NAD+ and arginine exert this effect by acting as signaling molecules, while carrying out other important cellular functions. Metabolites can also be involved in the control of cell proliferation by directly regulating gene expression in ways that are signaling pathway-independent, e.g. by direct activation of transcription factors or by inducing epigenetic processes. The fact that metabolites can affect the cancer process on so many levels suggests that the change in concentration of some metabolites that occurs in cancer cells could have an active role in the progress of the disease. CoMet, a fully automated Computational Metabolomics method to predict changes in metabolite levels in cancer cells compared to normal references has been developed and applied to Jurkat T leukemia cells with the goal of testing the following hypothesis: Up or down regulation in cancer cells of the expression of genes encoding for metabolic enzymes leads to changes in intracellular metabolite concentrations that contribute to disease progression. All nine metabolites predicted to be lowered in Jurkat cells with respect to lymphoblasts that were examined (riboflavin, tryptamine, 3-sulfino-L-alanine, menaquinone, dehydroepiandrosterone, alpha-hydroxystearic acid, hydroxyacetone, seleno-L-methionine and 5,6-dimethylbenzimidazole), exhibited antiproliferative activity that has not been reported before, while only two (bilirubin and androsterone) of the eleven tested metabolites predicted to be increased or unchanged in Jurkat cells displayed significant antiproliferative activity. These results: a) demonstrate that CoMet is a valuable method to identify potential compounds for experimental validation, b) indicate that cancer cell metabolism may be regulated to reduce the intracellular concentration of certain antiproliferative metabolites, leading to uninhibited cellular growth and c) suggest that many other endogenous metabolites with important roles in carcinogenesis are awaiting discovery.