Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
Division of Life Science, College of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
FEBS Open Bio. 2019 Sep;9(9):1580-1588. doi: 10.1002/2211-5463.12699. Epub 2019 Jul 23.
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.
药物重定位作为一种替代策略，已引起人们对发现和开发新型抗癌候选药物的关注。在这项研究中，我们筛选了 321 种 FDA 批准的药物对未辐照和辐照 MCF-7 细胞，结果表明，阿立哌唑是一种多巴胺受体 D2（D2R）部分激动剂，可增强 MCF-7 细胞的放射敏感性。出乎意料的是，D2R 选择性拮抗剂处理显著增强了阿立哌唑的放射增敏作用，并阻止了阿立哌唑诱导的 5'腺苷单磷酸激活蛋白激酶（AMPK）磷酸化。用 A769662 直接激活 AMPK 可削弱阿立哌唑的放射增敏作用。这些结果表明，阿立哌唑具有作为放射增敏药物的潜力。此外，防止 D2R/AMPK 激活可能会增强阿立哌唑在乳腺癌细胞中的抗癌作用。
