Co-treatment with Celecoxib or NS398 Strongly Sensitizes Resistant Cancer Cells to Antimitotic Drugs Independent of P-gp Inhibition.

Abstract

Inhibition of cyclooxygenase-2 (COX-2) has been investigated in clinical trials. Currently, NS398 and celecoxib are the most commonly used COX-2 inhibitors. The purpose of this study was to identify conditions that would increase the sensitivity of resistant cancer cells to antimitotic drugs. We tested whether COX-2 inhibitors can sensitize drug-resistant KBV20C cancer cells. We also compared the efficacy of NS398 with that of celecoxib. Both NS398 and celecoxib could sensitize KB and KBV20C cells to a similar extent, suggesting that COX-2 inhibitors could be used for sensitive, as well as resistant, cancer cells. We demonstrated that the NS398 and celecoxib sensitization mechanism is independent of the inhibition of p-glycoprotein (P-gp), suggesting that resistant KBV20C cells are sensitized through targeting of signaling pathways by both drugs. Furthermore, through using microscopic observation, assessment of cleaved poly ADP ribose polymerase (C-PARP) and annexin V staining we determined that both COX-2 inhibitors strongly sensitized resistant KBV20C cells to vinblastine (VIB) or paclitaxel (PAC) treatment. These results suggest that antimitotic drug-resistant cancer cells can be strongly sensitized by co-treatment with COX-2 inhibitors, without P-gp inhibitory activity. These findings provide important information regarding the sensitization of drug-resistant cells and indicate that COX-2 inhibitors may be used for potentially resistant cancer patients, without the toxic effects of P-gp inhibition.