Anti-Tumor Effects of Statins in Pancreatic Ductal Adenocarcinoma Cells

Area of Science:

• Oncology
• Pharmacology
• Biochemistry

Background:

• Pancreatic ductal adenocarcinoma (PDAC) presents limited therapeutic options.
• Statins, HMG-CoA reductase inhibitors, influence cellular processes like the mevalonate pathway, mitochondrial function, and redox balance.

Purpose of the Study:

• To systematically compare the efficacy of seven statins in patient-derived PDAC cell lines.
• To investigate the mechanistic responses of PDAC cells to statin treatment, focusing on viability, apoptosis, cell cycle, mitochondrial function, redox state, and metabolism.

Main Methods:

• MTT assays were used to assess statin viability effects across three PDAC cell lines (PDAC-1/2/3) at varying concentrations (5-20 µM) and time points (24-120 h).
• Mechanistic profiling involved Annexin V/7-AAD staining for apoptosis, cell-cycle analysis, mitochondrial membrane potential (Δψm) assessment, intracellular reactive oxygen species (ROS) measurement, and 1H-NMR metabolomics.

Main Results:

• Statins reduced PDAC cell viability in a concentration- and time-dependent manner; lipophilic statins were more potent than hydrophilic ones.
• Significant inter-tumoral heterogeneity was observed: PDAC-1 was highly sensitive, PDAC-3 intermediate, and PDAC-2 resistant.
• Sensitive cell lines (PDAC-1/3) exhibited G0/G1 cell-cycle arrest, Δψm depolarization, elevated ROS, and increased apoptosis. Resistant PDAC-2 showed ROS reduction and limited apoptosis despite Δψm loss.
• Metabolomic analysis revealed decreased glucose and amino acid utilization and reduced lactate secretion, with preserved line-specific metabolic profiles.

Conclusions:

• PDAC cell lines exhibit substantial heterogeneity in their response to statins.
• Statins demonstrate potential as chemosensitizing adjuvants, suggesting a role in functionally guided PDAC treatment strategies.