Anti-Tumor Effects of Statins in Pancreatic Ductal Adenocarcinoma Cells

Pancreatic ductal adenocarcinoma (PDAC) has limited effective therapeutic strategies. Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and may affect tumor cell fitness via the mevalonate pathway, mitochondrial function, and redox homeostasis. We systematically compared seven statins in patient-derived PDAC cell lines and related viability effects to mitochondrial, redox, cell-cycle, apoptotic, and metabolic responses. Statins were tested in three PDAC cell lines (PDAC-1/2/3) using MTT assays (5–20 µM; 24–120 h). Based on MTT responses, mechanistic profiling was performed after 72 h at 20 µM concentration using lipophilic statins, including apoptosis (Annexin V/7-AAD), cell-cycle distribution, mitochondrial membrane potential (Δψm), intracellular ROS, and 1H-NMR quantification of intracellular and extracellular metabolites. Statins reduced viability in a concentration- and time-dependent manner, with lipophilic statins more active than hydrophilic. PDAC-1 was highly sensitive, PDAC-3 intermediate, and PDAC-2 comparatively resistant. PDAC-1 and PDAC-3 showed G0/G1 accumulation, Δψm depolarization, reactive oxygen species (ROS) elevation, and Annexin V–positive apoptosis, whereas PDAC-2 (high basal ROS) showed ROS reduction and limited apoptosis despite Δψm loss. Metabolomics indicated reduced glucose and amino-acid utilization and lactate secretion while preserving line-specific metabolic fingerprints. PDAC cell lines display marked inter-tumoral heterogeneity in statin responses, supporting evaluation of statins as chemosensitizing adjuvants in functionally guided PDAC treatment strategies.