Selenate specifically sensitizes drug-resistant cancer cells by increasing apoptosis via G2 phase cell cycle arrest without P-GP inhibition

The purpose of this study was to identify conditions that will increase the sensitivity of drug-resistant cancer cells. Selenium derivatives have been shown to present anti-cancer properties in the clinic. Currently, selenate, selenite, selenomethionine (SeMet), methyl-selenocysteine (MSC), and methaneselenic acid (MSA) are the most common selenium derivatives used as drugs in humans. Herein, we tested whether these selenium derivatives can sensitize KBV20C cancer cells, which are highly resistant to anti-cancer drugs such as vincristine. All five drugs could sensitize KBV20C cells to the same extent as they sensitized the sensitive parent KB cells, suggesting that selenium-derived drugs can be used for drug-resistant cancer cells. We also observed that these drugs did not inhibit the P-glycoprotein (P-gp) pumping-out ability, suggesting that the sensitization by selenium-derived drugs does not depend on P-gp activity in resistant KBV20C cells. Interestingly, using a cell viability assay, microscopic observation, and Hoechst staining, we found that selenate highly sensitized drug-resistant KBV20C cells by activating the apoptotic pathway, when compared to sensitive KB cells. Furthermore, we investigated why selenate sensitizes resistant KBV20C cells. Selenate-induced toxicity was associated with an increase in G2-phase cell cycle arrest in KBV20C cells, suggesting that the selenate-induced increase in apoptosis resulted from cell cycle arrest in resistant KBV20C cells. Our findings may contribute to the development of selenate-based therapies for patients resistant to cancer drugs.