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

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Abstract 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. The aim of this study was to evaluate the cytotoxic and chemosensitizing effects of tigecycline in combination with clinically relevant PDAC chemotherapy regimens, namely FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin) and Gem-Pac (gemcitabine plus nab-paclitaxel). The individual components of these regimens were applied at clinically relevant molar ratios reflecting patient treatment protocols. 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 assay, BrdU incorporation, and CellTiter-Glo ® 3D assays, and spheroid growth dynamics were quantified by imaging-based area measurements after 3 days of treatment. Tigecycline enhanced the cytotoxic effects of both chemotherapy regimens in a concentration- and cell line-dependent manner, with a more pronounced effect observed in combination with Gem-Pac. In MTS assays, tigecycline converted otherwise chemoresistant cell lines (PaTu-8902, PANC-1, and MIAPaCa-2) into more responsive phenotypes, with the strongest sensitization observed in PaTu-8902 cells. Δ effect analysis further revealed that tigecycline-mediated sensitization to Gem-Pac occurred across a broad concentration range. Notably, this effect was evident even at lower, otherwise ineffective doses in Capan-2 cells. In contrast, the effect of tigecycline in combination with FOLFIRINOX was rather moderate and predominantly observed at higher concentrations. These trends were consistent with BrdU and 3D spheroid models, which supported the observed cell line-dependent differences in treatment response. Clinically relevant, tigecycline alone exhibited concentration-dependent cytotoxicity, with minimal effects at lower concentrations and more pronounced reductions in viability at higher doses. 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.

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