Sulfonylureas Glimepiride and Gliclazide Prevent Pancreatic Cancer Progression by Modulating Capn2 and Strengthening Tumor Immunotherapy

Diabetes and pancreatic cancer (PC) may concurrently affect the same individual. In such patients, receiving both anti-diabetic drugs and anti-tumor therapy is indispensable to control disease progression. In recent years, immunotherapy has brought significant advances in cancer treatment. However, as one of the most common classes of antidiabetic medications, the role of sulfonylureas (SUs) in PC remains largely unknown, and their clinical application in immunotherapy is still limited. A murine syngeneic Pan02 pancreatic cancer model was established to assess the impact of glimepiride and gliclazide combined with programmed cell death protein 1 antibody(PD1ab), respectively. Immunohistochemistry was conducted to examine the number of infiltrated CD8+ T cells. In vitro and in vivo assays, including the CCK8 and Transwell migration assays, were utilized to study the direct effects of glimepiride and gliclazide on human pancreatic cancer cells Panc-1. To explore the preliminary mechanism, bioinformatics analyses were performed, including bioinformatics analysis, Western Blot (WB), and lentiviral transduction and transfection. Treatment with the SUs glimepiride and gliclazide treatment alone significantly inhibited the proliferation of subcutaneously grafted Pan02 cells in C57BL6/c mice. Furthermore, both agents showed a potential therapeutic effect on PD1ab. IHC examination showed that gliclazide induced higher CD8+ T cell infiltration. In vitro experiments utilizing human pancreatic cancer cells Panc-1 demonstrated that glimepiride and gliclazide significantly suppressed tumor proliferation and migration. The in vivo results supported the above conclusion. Moreover, the bioinformatics results indicated that Capn2 may be the targets of SUs and was negatively associated with CD8+ T cell infiltration and were closely associated with overall survival or disease-free survival in PC patients. In-vitro and in-vivo experiments verified that Capn2 may mediate the therapeutic effects of SUs against PC. The study revealed that SUs may prevent tumor growth by modulating Capn2 and potentiating the therapeutic effect of PD1ab, which may hold potential for PC therapy. This study provides novel insights for the medical application of SUs and should be confirmed by clinical trials.