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.
Highlights
Cervical carcinoma ranks the third most common cancer in young women worldwide
We tested the expression of sphingosine kinase 2 (SphK2) in human cervical carcinoma cells
The quantitative real-time PCR assay results in Figure 1A confirmed that SphK2 mRNA expression level was high in both primary (“P1” and “P2”) and established (C33A) human cervical carcinoma cells, and its level was relatively low in the primary epithelial cells (Figure 1A)
Summary
Cervical carcinoma ranks the third most common cancer in young women worldwide. It is an important cause of cancer mortalities [1,2,3]. The potential anti-cancer activity of ABC294640 against human cervical carcinoma cells is tested here. The quantitative real-time PCR assay results in Figure 1A confirmed that SphK2 mRNA expression level was high in both primary (“P1” and “P2”) and established (C33A) human cervical carcinoma cells, and its level was relatively low in the primary epithelial cells (Figure 1A).
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