Resumen
Amino acid metabolism is aberrantly altered in pancreatic cancer (PC). Evidence suggests that circulating histidine (His) levels are low in PC. However, the role of His in modulating the progression of PC remains unknown. We determined the role of His in altering the therapeutic effectiveness of gemcitabine (Gem) against PC. We provide evidence that the expression of histidine ammonia lyase (HAL), an enzyme involved in His catabolism, is greatly increased in mouse and human pancreatic tumors. We show that combining His with Gem led to enhanced cytotoxic effects against aggressive PC cell lines. Our metabolomics analysis revealed that His treatment results in the depletion of amino acids supporting glutathione production. His depletes cellular glutathione and increased hydrogen peroxide production, indicating that His potentiates the cytotoxic effects of Gem by promoting oxidative stress. A combination of His and Gem was effective in attenuating pancreatic tumor growth and improving the survival of mice exhibiting xenograft tumors. Our findings suggest that His supplementation is an effective nutritional approach to enhance the efficacy of chemotherapeutic drugs.