Dopamine receptor D2 activation suppresses the radiosensitizing effect of aripiprazole via activation of AMPK

Drug repositioning has garnered attention as an alternative strategy to the discovery and development of novel anticancer drug candidates. In this study, we screened 321 FDA‐approved drugs against nonirradiated and irradiated MCF‐7 cells, revealing that aripiprazole, a dopamine receptor D2 (D2R) partial agonist, enhances the radiosensitivity of MCF‐7 cells. Unexpectedly, D2R‐selective antagonist treatment significantly enhanced the radiosensitizing effects of aripiprazole and prevented aripiprazole‐induced 5' adenosine monophosphate‐activated protein kinase (AMPK) phosphorylation. Direct AMPK activation with A769662 treatment blunted the radiosensitizing effects of aripiprazole. These results indicate that aripiprazole has potential as a radiosensitizing drug. Furthermore, prevention of D2R/AMPK activation might enhance these anticancer effects of aripiprazole in breast cancer cells. In this study, we identified aripiprazole, a dopamine receptor D2 (D2R) partial agonist, as a radiosensitizer in breast cancer cells. Unexpectedly, subsequent experiments showed a nullifying contribution of D2R/5' adenosine monophosphate‐activated protein kinase (AMPK) pathway to the radiosensitizing effects of aripiprazole. Thus, our results suggest that prevention of the D2R/AMPK activation might enhance the anticancer effects of aripiprazole in breast cancer cells.