Long-acting response of COX-2-mediated metastasis inhibition by oxaliplatin-based CP-L-OHP

Abstract

Gastric adenocarcinomas present elevated cyclooxygenase-2 (COX-2) expression compared to non-neoplastic mucosa. Four oxaliplatin (L-OHP)-based Pt(IV) complexes, CP-L-OHP (1), ED-L-OHP (2), KP-L-OHP (3), and SL-L-OHP (4), were synthesized with the non-steroidal anti-inflammatory drugs (COX inhibitors) carprofen, etodolac, ketoprofen and sulindac, respectively, as axial ligands to inhibit BGC-823 gastric cancer cells. Complexes 1–4 displayed comparable cytotoxicity to L-OHP, of which 1 displayed the lowest IC₅₀ value and best selectivity in BGC-823 cells compared to normal liver cells (LO2). Complex 1 significantly enhanced Pt accumulation, DNA damage and apoptosis in BGC-823 cells. Overexpression of COX-2 can lead to a more aggressive behavior in gastric cancer, inducing metastatic and invasive processes. The wound-healing assay displayed that 1 could significantly delay BGC-823 cell metastasis with the lowest wound-healing rate compared to L-OHP and carprofen after treatment for 24 h. Interestingly, few 1-treated cells were observed to adhere to Matrigel, while the cell adhesion was hardly affected by the other treatment groups such as carprofen in cell adhesion experiments. Immunofluorescence studies indicated that 1 exhibited a longer-acting COX-2 response than carprofen alone. Carprofen (20 μM) effectively inhibited COX-2 at 1 and 5 h of treatment in BGC-823 cells, but did not work at 24 h. In contrast, 1 could retain the high inhibitory activity against COX-2 up to 24 h at least.