Low-Dose Oxaliplatin Enhances The Antitumor Efficacy Of Paclitaxel In Human Gastric Cancer Cell Lines

Background: The enhanced anti-tumor effect of paclitaxel combined with oxaliplatin to treat gastric cancer has been reported; however, the underlying biological mechanism is still unknown.Methods: We tested the cytotoxic activity of paclitaxel plus oxaliplatin by a WST-1 assay in MKN-28 and MKN-45 gastric cancer cell lines. We evaluated chemotherapy-induced apoptosis and mitotic catastrophe by flow-cytometry and hematoxylin nuclear staining, respectively. The modulation of survivin expression was determined by Western blotting.Results: WST-1 assay showed that paclitaxel combined with oxaliplatin had better cytotoxicity than paclitaxel alone, even when low concentrations of oxaliplatin were used. Flow-cytometry analysis revealed significantly greater increases in apoptotic cells after treatment with paclitaxel (IC₅₀ value) followed by low-dose oxaliplatin (1μM) than after any single-reagent regimen (IC50 value) in the MKN-45 cell line. In the MKN-28 cell line, a difference existed only between combination treatment and oxaliplatin treatment. Morphologic examination showed that the cells undergoing mitotic catastrophe were highest in the combination groups. Down-regulated survivin expression was found by Western blotting after treatment with paclitaxel followed by low-dose oxaliplatin (1μM).Conclusion: Our findings suggest that the mechanism of enhanced cytotoxicity might involve chemotherapy-induced down-regulation of survivin protein levels, which promote mitotic catastrophe, apoptosis, or both, and the resultant anti-cancer activity. The combination of paclitaxel and low dose oxaliplatin should be incorporated into the design of a clinical trial.