Tigecycline Enhances Sensitivity to FOLFIRINOX and Gemcitabine/Nab-Paclitaxel in In Vitro Models of Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies and remains highly resistant to systemic chemotherapy. Tigecycline, a glycylcycline antibiotic that inhibits mitochondrial translation, has recently attracted attention as a potential candidate for drug repurposing in oncology because of its proposed chemosensitizing effects. In this study, we investigated the cytotoxic and chemosensitizing effects of tigecycline in combination with the clinically used PDAC chemotherapy regimens FOLFIRINOX and gemcitabine plus nab-paclitaxel (Gem-Pac). Experiments were performed using both 2D monolayer cultures and 3D spheroid models of four PDAC cell lines (PaTu-8902, PANC-1, MIAPaCa-2, and Capan-2). Cell viability and proliferation were assessed using MTS, BrdU incorporation, and CellTiter-Glo® 3D assays, and spheroid growth dynamics were quantified by imaging-based area measurements after 3 days of treatment. Tigecycline showed limited cytotoxicity as a single agent but moderately enhanced the antiproliferative effects of FOLFIRINOX in a cell-line-dependent manner, while a more pronounced and consistent chemosensitizing effect was observed in combination with Gem-Pac, particularly in PaTu-8902 and PANC-1 models. These effects were reproducible across independent assays and were most evident in 3D spheroids, where tigecycline markedly suppressed chemotherapy-induced spheroid growth. Overall, these findings demonstrate that tigecycline can enhance the efficacy of clinically relevant PDAC chemotherapy regimens in vitro and support its further preclinical evaluation as a potential adjunct to existing PDAC treatment strategies.