A single treatment of Selenate, a repositioning drug, specifically sensitizes P-gp-overexpressing resistant cancer cells

Abstract

We investigated possible conditions or drugs that might enhance the sensitivity of anti-mitotic drug-resistant cancer cells. We particularly focused on identifying mechanisms or drugs that could sensitize P-glycoprotein (P-gp)-overexpressing resistant KBV20C cancer cells. Our approach utilized repositioning drugs, which are already used in clinics, because once their sensitization mechanisms on resistant cancer cells are known, they would be readily applied without further toxicity studies. Selenium-derived drugs such as selenate, selenite, selenomethionine (SeMet), methyl-selenocysteine (MSC), and methaneselenic acid (MSA) have been shown to have anti-cancer properties clinically. The type of selenium-derived drug that can specifically sensitize P-gp-overexpressing resistant KBV20C cancer cells was investigated for further application in the clinical settings. We recently reported five selenium-derived drugs that could sensitize both resistant KBV20C and KB parent sensitive cancer cells without P-gp inhibition. Among these five drugs, our study highlights the unprecedented finding of the selective sensitization ability of selenate against P-gp-overexpressed resistant KBV20C cells. Detailed analysis indicates that selenate is a resistant cancer cell-specific sensitizing drug that increases apoptosis via G2-phase cell cycle arrest. These results may help improve chemotherapeutic treatments based on selenium-derived drugs for cancer patients who develop resistance to anti-mitotic drugs.