Targeted ¹³C-labeled tracer fate associations for drug efficacy testing in cancer

Metabolomics technologies continue to develop not only to study endpoint steady-state concentrations of numerous metabolites in normal and cancer cells but also to examine metabolic flux and networks. These techniques are of importance for understanding tumor cell metabolism and for the development of new drugs and treatment strategies. The choice of tracer substrates is central as ¹³C-labeled substrates readily improve real-time reaction visibility by increasing metabolic network transparencies in cancer metabolomics. In this chapter, targeted [1,2- ¹³C₂]-d-glucose single tracer fate associations are compared with the external [U- ¹³C₁₈]-stearate oxidation model for thiazolidinedione efficacy testing in primary liver tumor cells. Although the externally supplied [U- ¹³C₁₈]-stearate tracer readily labels multiple products by acetyl-CoA exchange, parallel stearate synthesis and mobilization from unlabeled intracellular pools disrupt its uptake after drug treatment. This can be overcome by using cross-labeled ¹³C-stearate from [1,2- ¹³C₂]-d-glucose as the internal tracer and the independent explanatory variable to study associations among markers of rosiglitazone-induced stearate breakdown in a single [1,2-¹³C₂]-d-glucose tracer experiment during drug efficacy testing in cultured cells.