Src is the primary target of aripiprazole, an atypical antipsychotic drug, in its anti-tumor action
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Mi Seon Kim1,*, Byong Chul Yoo2,*, Woo Seok Yang1,*, Sang Yun Han1, Deok Jeong1, Jun Min Song3, Kyung Hee Kim2, Adithan Aravinthan4, Ji Hye Kim1, Jong-Hoon Kim4, Seung Cheol Kim5 and Jae Youl Cho1
1Department of Genetic Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea
2Colorectal Cancer Branch, Research Institute, National Cancer Center, Goyang 10408, Republic of Korea
3School of Medicine, Keimyung University, Daegu 42601, Republic of Korea
4Department of Physiology, College of Veterinary Medicine, Chonbuk National University, Iksan 54596, Republic of Korea
5Department of Obstetrics and Gynecology, Ewha Womans University Mokdong Hospital, Ewha Womans University School of Medicine, Seoul 07985, Republic of Korea
*These authors contributed equally to this work
Jong-Hoon Kim, email: [email protected]
Seung Cheol Kim, email: [email protected]
Jae Youl Cho, email: [email protected]
Keywords: aripiprazole; antipsychotic drug; antitumor activity; apoptosis; Src
Received: September 19, 2017 Accepted: December 01, 2017 Published: December 08, 2017
Aripiprazole (ARP) is an atypical anti-psychotic drug widely used to treat schizophrenia and bipolar disorder. The pharmacological effects of ARP on cancer cells are still poorly understood. In this study, anti-cancer effects of ARP on various malignant tumor cells and its molecular mechanism were further carefully examined by using cell proliferation assay, xenograft mouse model, immunoblotting analysis, migration assay, luciferase reporter gene assay, kinase assay, and overexpression strategy. Treatment with ARP induced cytotoxicity in U251 glioma cells, MKN-1 gastric adenosquamous carcinoma cells, and CT26 colon carcinoma cells. ARP suppressed cell proliferation of LN428, MDA-MB-231, and HEK293 cells. Pro-apoptotic factors active caspase-3, -8, and -9, as well as p53, were upregulated, whereas the protein and mRNA levels of anti-apoptotic factor B-cell lymphoma 2 (Bcl-2) decreased. In agreement with the in vitro results, ARP compound also significantly suppressed the growth of tumor masses formed by injecting CT26 colon cancer cells into mice. ARP treatment also effectively decreased the migratory ability of U251 glioma cells by downregulating metalloproteinase-9. Levels of phosphorylated Src, phosphorylated phosphatidylinositide 3-kinase (PI3K), and phosphorylated signal transducer and activator of transcription 3 (STAT3) were significantly decreased following ARP treatment. ARP compound reduced the kinase activity of Src. Our studies suggest that Src may be an important target molecule linked to the antitumor effects of ARP.
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