Pancreatic ductal adenocarcinoma (PDAC) is predicted to be the second leading cause of cancer related deaths by 2030. Gemcitabine is a common chemotherapeutic drug used to treat PDAC, yet it is prone to chemoresistance. In this study, we tested the effectiveness of the combined treatment of gemcitabine and histidine, an essential amino acid, as a means of reducing chemoresistance and increasing cytotoxicity. Effects of this combined treatment were determined by analyzing glucose metabolism in two different mouse experiments (tumor tissue and serum). An NMR-based metabolomics workflow was used to complete statistical analysis and metabolite identification/alterations. Tissue and serum samples demonstrated metabolic alterations following treatment with either histidine only (HIS) or a combination of both histidine and gemcitabine (HIS+GEM). Important glutathione producing metabolites were observed in reduced concentrations when treated with HIS and HIS+GEM. The combined HIS+GEM treatment also altered glycogenesis metabolites, which were observed to increase in the pancreatic tumor tissue. These results, in combination with previous studies, suggest a HIS+GEM treatment induced increased oxidative stress by altering glutathione precursors. We hypothesize that histidine enhances the cytotoxicity of gemcitabine, which ultimately leads to an increase in PDAC apoptosis. Future efforts will focus on identifying the precise mechanism of action for histidine when combined with gemcitabine. Understanding these mechanisms and the associated metabolic alterations will contribute to improved PDAC treatments and better cancer therapies.

Histidine and gemcitabine treatment demonstrates synergistic effects in pancreatic cancer

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