Redox, lipid, and metabolic changes associated with early tolerance to combination chemotherapy in two pancreatic cancer cell models
Year: 2026
Type: article
Abstract: Pancreatic ductal adenocarcinoma (PDAC) shows limited responsiveness to chemotherapy and rapidly develops resistance, which can be facilitated by early adaptive tolerance to sub-lethal drug exposure. Here, we investigated changes associated with the development of early tolerance to a chemotherapy combination analogous in composition to FOLFIRINOX in MIA PaCa-2 and PANC-1 cells using a stepwise adaptation approach. Comparison of metabolic similarities and divergences between the two cell lines by dose-response analysis revealed limited, yet progressive and cell-specific, shiftsin drug sensitivity. At the consolidated stage, Nile Red imaging and targeted lipidomics revealed cell line-specific lipid remodeling, including elongation of membrane phospholipid acyl chains in both lines. PANC-1 cells show increased saturation of phosphatidylcholine and triacylglycerols and reduced polyunsaturation of phosphatidylethanolamine and phosphatidylcholine. Antioxidant profiling also shows model-dependent patterns: MIA PaCa-2 cells exhibit increased total catalase, total glutathione S-transferase, and glutathione reductase activities, whereas PANC-1 cells show reduced catalase activity together with increased total glutathione S-transferase activity. These changes are accompanied by increased cytosolic and mitochondrial oxidation-dependent fluorescence in MIA PaCa-2 cells and reduced mitochondrial oxidation-dependent fluorescence in PANC-1 cells. MIA PaCa-2 cells also showed reduced extracellular lactate production, while cellular energy charge remained unchanged in both models. Whether these adaptations can be exploited therapeutically remains to be tested; they nevertheless identify redox- and lipid-related pathways as candidates for functional studies aimed at preventing the transition from tolerance to stable resistance.
Source: Scientific Reports
Institutions: University of Pisa, Istituto di Fisiologia Clinica
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,690
OpenAlex ID: W7225627889
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