The sphingosine kinase 2 inhibitor ABC294640 inhibits cervical carcinoma cell growth

// Ling Xu 1, * , Longmei Jin 2, * , Baohua Yang 1, * , Lifeng Wang 1 , Ziyin Xia 1 , Qian Zhang 3 and Jun Xu 1 1 Department of Obstetrics and Gynecology, Minhang Branch, Zhongshan Hospital, Fudan University, Shanghai, China 2 Minhang District Maternal and Child Health Hospital, Shanghai, China 3 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, China * Co-first authors Correspondence to: Jun Xu, email: xujunminh81@163.com Qian Zhang, email: qzhangfud75@163.com Keywords: cervical carcinoma; sphingosine kinase 2; ABC294640; Bcl-2; ceramide Received: October 26, 2017     Accepted: December 05, 2017     Published: December 19, 2017 ABSTRACT ABC294640 is a specific sphingosine kinase 2 (SphK2) inhibitor. The anti-cervical carcinoma activity by ABC294640 was tested in this study. ABC294640 inhibited in vitro growth of the established (C33A and HeLa lines) and primary human cervical carcinoma cells. The SphK2 inhibitor also induced G1-S arrest and apoptosis in cervical carcinoma cells. It was yet non-cytotoxic to SphK2-low human cervical epithelial cells. ABC294640 inhibited SphK activation, causing sphingosine-1-phosphate depletion, signal transducer and activator of transcription 3 in-activation and ceramide production. Bcl-2 is a key resistance factor of ABC294640. Pharmacological Bcl-2 inhibition or Bcl-2 shRNA potentiated ABC294640-induced C33A cell growth inhibition and apoptosis. On the other hand, exogenous over-expression of Bcl-2 attenuated ABC294640’s cytotoxicity against C33A cells. In vivo , ABC294640 administration inhibited C33A xenograft tumor growth in mice. Co-administration of the Bcl-2 inhibitor GDC-0199 further potentiated ABC294640’s anti-tumor activity. Together, we suggest that ABC294640 might have translational value for the treatment of human cervical carcinoma.