METABOLIC AND ENZYMATIC ALTERATIONS IN PANCREATIC DUCTAL ADENOCARCINOMA CELL LINES EXPOSED TO SUBLETHAL DOSES OF CHEMOTHERAPIC DRUGS

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the Western world. Despite rising incidence rates, the mortality rate has not significantly declined due to late diagnosis, early metastasis, and limited responses to chemotherapy and radiotherapy. Adjuvant chemotherapy, typically used after surgical resection, is the main treatment for early-stage pancreatic cancer. Treatments like FOLFIRINOX (5-fluorouracil/leucovorin, irinotecan, oxaliplatin) and gemcitabine/paclitaxel can improve outcomes for advanced pancreatic cancer, but chemoresistance still leads to poor results. Chemoresistance is promoted by the tumor's heterogeneous composition, including cancer cells, cancer stem cells, and the tumor microenvironment. The cell redox system is thought to be involved in the development of this resistance, although the role of different metabolic pathways remains unclear and may vary by cell line. The aim of this study is to investigate the mechanisms of chemoresistance in PDAC by generating three chemoresistant cell lines resistant to FOLFIRINOX. The process began by evaluating cell viability with increasing drug concentrations to determine the IC50 for each line. Cells were gradually exposed to the drug, and analyses were conducted at each stage to measure oxidative stress and enzyme activity, such as superoxide dismutase, catalase, glutathione S-transferase, and glutathione reductase. Variations in enzyme levels and redox state were correlated with changes in treatment sensitivity.