Sphingosine kinase 2 inhibitor ABC294640 displays anti-epithelial ovarian cancer activities in vitro and in vivo
Authors Song K, Dai L, Long X, Cui X, Liu Y, Di W
Received 13 March 2019
Accepted for publication 24 April 2019
Published 6 June 2019 Volume 2019:12 Pages 4437—4449
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Ms Shreya Arora
Peer reviewer comments 2
Editor who approved publication: Dr Takuya Aoki
Keqi Song,1,2,* Lan Dai1,2,* Xiaoran Long,1,2 Xiaojuan Cui,3 Yixuan Liu,1,2 Wen Di1,2,4
1Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, People’s Republic of China; 2Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, People’s Republic of China; 3Department of Obstetrics and Gynecology, Rui Jin Hospital & Ruijin Hospital North, School of Medicine, Shanghai Jiao Tong University, Shanghai 201801, People’s Republic of China; 4State Key Laboratory of Oncogene and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, People’s Republic of China
*These authors contributed equally to this work
Background: ABC294640 is a non-lipid competitive inhibitor of SphK2. It exhibited anti-proliferative activities in many human malignancies, including ovarian cancer. However, its potential mechanism of action remains poorly understood.
Methods: In this paper, epithelial ovarian cancer (EOC) cell lines SKOV3 and HO8910 were treated with ABC294640. In order to explore the effect of ABC294640 on the behavior of ovarian cancer cells in vitro, we used cell counting kit-8 (CCK-8) assays, colony formation assays, flow cytometry, quantitative real-time PCR (qRT-PCR), Western blot analysis and immunohistochemistry to detect the effect of ABC294640 on cell proliferation, cell cycle distribution, cell apoptosis, the expression of related factors at mRNA levels, and the expression of related factors at protein level. An intra-abdominal xenograft tumor model of EOC was set up to assess the tumor growth in nude mice.
Results: The results obtained indicate that EOC cell proliferation was noticeably inhibited in a concentration-dependent manner by ABC294640. ABC294640 caused cell cycle arrest in S phase and increased cell apoptosis rate in EOC cells. Also, the proteins, including phosphorylated retinoblastoma protein (P-Rb), cyclin D1, cyclin B1, and Bcl-2 were significantly inhibited, while cleaved-caspase 3 was activated. ABC294640 inhibited the expression of c-Myc in EOC. The in vivo assay showed an inhibitory effect of ABC294640 on tumor growth.
Conclusions: ABC294640 could downregulate the expression of c-Myc in EOC both in vitro and in vivo. ABC294640 inhibited tumor growth in EOC via cell cycle arrest and inducing cell apoptosis both in vitro and in vivo, partially by decreasing the expression of cell cycle–associated proteins (such as P-Rb, cyclin B1, and cyclin D1) and promoting caspase 3 activation via downregulation expression of c-Myc. It suggested that ABC294640 had the potential to serve as an agent in EOC treatment.
Keywords: ABC294640, epithelial ovarian cancer, c-Myc, proliferation
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