PT - JOURNAL ARTICLE AU - JI YEONG KIM AU - JI YEON SON AU - BYUNG-MU LEE AU - HYUNG SIK KIM AU - SUNGPIL YOON TI - Aging-related Repositioned Drugs, Donepezil and Sildenafil Citrate, Increase Apoptosis of Anti-mitotic Drug-resistant KBV20C Cells Through Different Molecular Mechanisms AID - 10.21873/anticanres.12837 DP - 2018 Sep 01 TA - Anticancer Research PG - 5149--5157 VI - 38 IP - 9 4099 - http://ar.iiarjournals.org/content/38/9/5149.short 4100 - http://ar.iiarjournals.org/content/38/9/5149.full SO - Anticancer Res2018 Sep 01; 38 AB - Background/Aim: The study focused on identifying the mechanisms or drugs that could sensitize P-glycoprotein (P-gp)-overexpressing resistant KBV20C cancer cells to halaven (HAL) or vincristine (VIC) treatment. Materials and Methods: Based on the relatively low dose or IC50 values for sensitizing anti-mitotic drug-resistant KBV20C cells, the aging-related drugs donepezil (DON) and sildenafil citrate (SID) were selected. Fluorescence-activated cell sorting (FACS), western blotting, and annexin V analyses were performed to investigate the mechanism of action of DON and SID in HAL-treated KBV20C cells. Results: DON or SID reduced cell viability, increased G2 arrest, and up-regulated the expression of the DNA damaging protein pH2AX when used as co-treatment with HAL. DON and SID induced both early and late apoptosis in KBV20C cells in response to HAL treatment, without increasing autophagy. VIC-DON and VIC-SID co-treatments increased sensitization of KBV20C cells, suggesting that DON and SID can be combined with other anti-mitotic drugs for sensitizing resistant cancer cells. When the sensitization efficacies of DON and SID were compared to that of the anti-psychotic repositioned drug fluphenazine (FLU), HAL-SID or HAL-FLU co-treatments were found to have better sensitization effects than HAL-DON suggesting that HAL-SID sensitization mechanism is different from that of HAL-DON. In addition, DON was found to have higher P-gp inhibitory activity than FLU or SID. Conclusion: These results suggest that HAL-FLU or HAL-SID sensitization in KBV20C cells involves both cytotoxic and P-gp inhibitory effects, whereas HAL-DON sensitization may involve only P-gp inhibitory activity of DON.