Sijunzi Tang improves gefitinib resistance by regulating glutamine metabolism

Lung cancer is a major health concern and significant barrier to human well-being and social development. Although targeted therapy has shown remarkable progress in the treatment of lung cancer, the emergence of drug resistance has limited its clinical efficacy. Sijunzi Tang (SJZ) is a classical Chinese herbal formula known for tonifying qi and nourishing the lungs, has been recognized for its potential in lung cancer management. However, the underlying mechanism of its combined use with anti-cancer drugs remains unclear. Here, we investigated the anti-lung cancer efficacy and underlying mechanisms of the combination of gefitinib and SJZ in gefitinib-resistant human lung adenocarcinoma cells (PC-9/GR). We conducted in vitro and in vivo experiments using histopathology and targeted metabolomics approaches. Our results demonstrated that the combination of SJZ and gefitinib exhibited synergistic effects on tumor growth inhibition in PC-9/GR-bearing nude mice. Notably, the co-administration of SJZ and gefitinib synergistically promoted tumor cell apoptosis, potentially through the regulation of BAX and BCL-2 expression. Immunohistochemistry and western blot analysis found down-regulation of GLS, GS, and SLC1A5 expression in the co-administration group compared to the control and the individual treatment groups. Targeted metabolomics revealed significant alterations in the plasma glutamine metabolic markers glutamine, alanine, succinate, glutamate, and pyruvate. Of the glutamine metabolism markers measured in tumor tissues, glutamine and pyruvate demonstrated significant differences across the treatment groups. These findings suggest that administration of SJZ improves gefitinib resistance in the treatment of lung cancer without toxic effects. Moreover, SJZ may affect glutamine metabolism by regulating key targets involved in glutamine metabolism (SLC1A5, GLS, and GS) and modulating the levels of related metabolic markers, ultimately reducing gefitinib resistance.