Highly Halaven-resistant KBV20C Cancer Cells Can Be Sensitized by Co-treatment with Fluphenazine

To identify conditions that induce an increase in the sensitivity of highly Halaven (HAL)-resistant cancer cells compared to sensitive cells. We observed that drug-resistant KBV20C cells are highly resistant to HAL compared to other antimitotic drugs. The concentration required to treat KBV20C cells was almost 500-fold higher than that used to treat sensitive parent KB cells. In order to increase sensitization, HAL-treated KBV20C cells were co-treated with the repositioned drug, fluphenazine (FLU). HAL and FLU co-treatment inhibited the growth and increased apoptosis via G arrest in HAL-treated KBV20C cancer cells. Sensitization by HAL-FLU affected retinoblastoma protein (pRB), pHistone H3 and pH2AX protein levels. FLU could also inhibit p-glycoprotein (P-gp) activity in HA-resistant KBV20C cells. These observations suggest that the mechanisms underlying FLU-HAL sensitization in resistant KBV20C cells involve both apoptosis and P-gp inhibition. Furthermore, both thioridazine (THIO) and mefloquine (MEF), but not azathioprine (AZA), sensitized HAL-treated KBV20C cells. These findings provide important information regarding the sensitization of HAL-resistant cells and indicate that FLU, THIO and MEF may have similar sensitization effects in highly HAL-resistant cells.