Valproic acid inhibits gastric cancer cell hallmarks but impairs wound healing in a PIPAC-inspired in vitro model

Abstract Objectives Valproic acid (VPA), a histone deacetylase inhibitor, has been proposed for pressurized intraperitoneal aerosol chemotherapy (PIPAC) to prevent peritoneal recurrence of gastric cancer while theoretically sparing wound healing. We tested this hypothesis using a PIPAC-inspired in vitro model. Methods MKN-45 gastric cancer cells, neonatal human dermal fibroblasts (NHDF), and mesothelial cells (MeT-5A) were exposed to aerosolized VPA (0.126–2.5 mg/mL), paclitaxel (PTX; 3 μg/mL), or their combinations for 30 min under pressurized conditions. Outcomes included cytotoxicity (CASY cell counting), metabolic activity (MTT assay), cell migration and wound healing (scratch assays), and adhesion to extracellular matrix proteins. Results VPA alone exerted only modest, delayed, and largely concentration-independent antiproliferative effects, with no clear dose–response relationship across the tested range. Metabolic inhibition emerged at concentrations ≥1.5 mg/mL and became profound at ≥2 mg/mL. VPA concentration dependently inhibited cancer cell migration and adhesion to all ECM substrates tested. However, VPA also completely prevented wound closure in normal fibroblasts and mesothelial cells at concentrations as low as 0.252 mg/mL. Combining VPA (1.5 mg/mL) with PTX (3 μg/mL) did not significantly exceed the activity of PTX alone in cytotoxicity (p=0.76) or metabolic assays (p=0.89), with no consistent synergy observed under the fixed-dose conditions tested. Conclusions Although VPA delivered via PIPAC inhibits selected gastric cancer hallmarks, its antiproliferative activity is weak in MKN-45 cells, and the concentrations required for antitumor effects are substantially higher than clinically achievable serum levels. Importantly, VPA impairs wound healing in normal peritoneal-relevant cells, challenging its proposed utility as a recurrence-preventing agent that spares the healing peritoneum. The VPA–PTX combination did not show consistent synergy, and further studies with additional gastric cancer cell lines and in vivo models are warranted.