Preclinical study of CC223 as a potential anti-ovarian cancer agent

// Zhenzhen Jin 1, * , Huanfu Niu 1, * , Xuenan Wang 1 , Lei Zhang 2 , Qin Wang 1 and Aijun Yang 1 1 Center for Reproductive Medicine, Affiliated Hospital of Jining Medical University, Jining, China 2 Department of Pathology and Laboratory Medicine, Clinical Microarray Core, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA * Co-first author Correspondence to: Aijun Yang, email: yajjiningmd@163.com , yajlws2017@163.com Keywords: ovarian cancer, mTOR, CC223, signaling Received: April 12, 2017      Accepted: April 25, 2017      Published: May 10, 2017 ABSTRACT Aberrant activation of mTOR contributes to ovarian cancer progression. CC223 is a novel and potent mTOR kinase inhibitor. The current study tested its activity against human ovarian cancer cells. We showed that CC223, at nM concentrations, inhibited survival and proliferation of established/primary human ovarian cancer cells. Further, significant apoptosis activation was observed in CC223-treated ovarian cancer cells. CC223 disrupted assembly of mTOR complex 1 (mTORC1) and mTORC2 in SKOV3 cells. Meanwhile, activation of mTORC1 and mTORC2 was almost completely blocked by CC223. Intriguingly, restoring mTOR activation by introduction of a constitutively-active Akt1 only partially inhibited CC223-induced cytotoxicity in SKOV3 cells. Further studies showed that CC223 inhibited sphingosine kinase 1 (SphK1) activity and induced reactive oxygen species (ROS) production in SKOV3 cells. At last, oral administration of CC223 potently inhibited SKOV3 xenografted tumor growth in nude mice. The results of this study imply that CC223 could be further studied as a potential anti-ovarian cancer agent.