Targeted Cepharanthine-Mediated Dual-Pathway Inhibition Sensitizes Pancreatic Cancer to Gemcitabine.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, and gemcitabine (GEM) resistance is a major contributor to its poor clinical outcomes, generating an urgent need for novel therapeutic strategies targeting tumor proliferation and tumor-cell-intrinsic malignant signaling. This study aimed to investigate the synergistic anti-PDAC efficacy and underlying mechanism of cepharanthine (CEP) combined with GEM. A series of in vitro and in vivo experiments were performed to evaluate the antitumor activity, synergistic effect and preliminary in vivo safety of the CEP-GEM combination. Bioinformatics analysis coupled with experimental validation was applied to dissect the underlying mechanisms. The results demonstrated that CEP produced marked synergistic effects with GEM to suppress PDAC growth both in vitro and in vivo. Mechanistic investigations revealed that CEP blocked the PI3K/AKT/mTOR pathway and reduced tumor-cell-intrinsic PD-1/PD-L1 levels, thereby facilitating tumor-cell apoptosis, restraining cell migration and invasion, and sensitizing GEM-relatively insensitive AsPC-1 cells to GEM. Under our experimental conditions, no obvious histopathological injury or prominent systemic toxicity was observed. In conclusion, this work provides preclinical evidence showing that the CEP-GEM combination exerts anti-tumor activity via dual-pathway suppression in PDAC cells, and supports further translational research for PDAC.