Thioridazine inhibits angiogenesis and tumor growth by targeting the VEGFR-2/PI3K/mTOR pathway in ovarian cancer xenografts

// Mi Sun Park 1,* , Seung Myung Dong 1,* , Boh-Ram Kim 1 , Seung Hee Seo 1 , Sokbom Kang 1 , Eun-Ju Lee 2 , Seung-Hoon Lee 3 and Seung Bae Rho 1 1 Research Institute, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, Goyang-si Gyeonggi-do, Republic of Korea 2 Department of Obstetrics and Gynecology, Chung-Ang University School of Medicine/Chung-Ang University Hospital, Seoul, Republic of Korea 3 Department of Life Science, Yong In University, 470, Samga-dong, Cheoin-gu, Yongin-si Gyeonggi-do, Republic of Korea * These Authors contributed equally to this work Correspondence: Seung Bae Rho, email: // Keywords : thioridazine, anti-tumor effect, anti-angiogenic activity, mTOR signaling, xenograft model Received : April 16, 2014 Accepted : June 5, 2014 Published : June 6, 2014 Abstract Thioridazine, a member of the phenothiazine family, is a powerful anti-anxiety and anti-psychotic drug. It can also suppress the growth of several types of tumor in vitro . In the current study, we evaluated the direct anti-tumor and anti-angiogenic effects of thioridazine in vivo . The injection of thioridazine into human ovarian tumor xenografts in nude mice significantly inhibited tumor growth by ~fivefold, and also decreased tumor vascularity. In addition, thioridazine inhibited the phosphorylation of the signaling molecules downstream of phosphatidylinositol-3’-kinase (PI3K), including Akt, phosphoinositide-dependent protein kinase 1 (PDK1), and mammalian target of rapamycin (mTOR), during ovarian tumor progression via vascular endothelial growth factor receptor 2 (VEGFR-2). These results provide convincing evidence that thioridazine regulates endothelial cell function and subsequent angiogenesis by inhibiting VEGFR-2/PI3K/mTOR signal transduction. Collectively, these results strongly suggest that thioridazine might be a novel anti-tumor and anti-angiogenic agent for use in ovarian cancer.