Computational and experimental evaluation of curcumin as a DNMT3B-targeting epigenetic modulator in pancreatic cancer.

Abstract

Pancreatic cancer remains a therapeutic challenge due to its aggressive nature and resistance to conventional therapies. This study investigates the epigenetic effects of curcumin on the miR-29b/DNMT3B/MUC1 axis in pancreatic cancer cells (MIA PaCa-2) through an integrated bioinformatics and experimental approach. In silico analyses, including molecular docking and a preliminary 10 ns molecular dynamics simulation, indicated a plausible binding pose of curcumin within DNMT3B's catalytic site (binding energy: - 4.72 kcal/mol), with key interactions at residues GLU585 and ASN718, suggesting short-term binding persistence. In vitro experiments demonstrated that curcumin (IC₅₀ = 32.1 μM) significantly upregulated miR-29b (1.27-fold, p < 0.05), downregulated DNMT3B (63% reduction) and MUC1 (78% reduction), and induced ROS-dependent apoptosis (240% increase in ROS at 60 μM, p < 0.0001). DAPI staining confirmed nuclear fragmentation and apoptotic body formation, while minimal toxicity was observed in normal HUVEC cells. ADMET analysis highlighted curcumin's favorable pharmacokinetic profile, including oral bioavailability (HIA ≈ 0.78) and low toxicity. These findings underscore curcumin's dual role as an epigenetic modulator (via miR-29b/DNMT3B/MUC1) and ROS inducer, offering a promising strategy for targeted pancreatic cancer therapy.