The sphingosine kinase 2 inhibitor ABC294640 inhibits cervical carcinoma cell growth

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.

Bioactive compounds from the seeds of Amomum tsaoko Crevost et Lemaire, a Chinese spice as inhibitors of sphingosine kinases, SPHK1/2

“…2). Of note, among the isolates, an acetylated aliphatic alcohol (2), a fatty acid (5), and two phenolics (10)(11) were identied as new compounds, and compound 1 was isolated for the rst time from natural sources.…”

“…In some cells, SPHK2 decreases cell cycle arrest, thus inhibition of SPHK2 induces cell cycle arrest and apoptosis and thus may exert anticancer effects. 4,5 Since sphingosines and ceramides play important roles in cell cycle arrest and apoptosis and S1P functions in cell proliferation, survival, differentiation, and angiogenesis, the inhibition of SPHK1/2 may induce cell cycle arrest and apoptosis by reducing S1P levels and increasing sphingosines and ceramides, which may be benecial for the treatment of various cancers. 6,7 SPHK1/2 inhibitors can thus exhibit anti-cancer activities directly or indirectly through sphingosine metabolism.…”

“…Bioactivity-based analysis and chemical investigation of the EtOH extract led to the isolation and iden-tication of 25 compounds . Compound 1 was identied from natural sources for the rst time and an acetylated aliphatic alcohol (2), a fatty acid (5), and two phenolics (10)(11) were identied as new compounds based on structural analysis using spectroscopic techniques including 1D and 2D nuclear magnetic resonance (NMR) and high-resolution electrospray ionization mass spectrometry (HR-ESIMS) as well as LC/MS analysis. The absolute congurations of new compounds were determined by quantum chemical electronic circular dichroism (ECD) calculations and the application of the recently developed method, competing enantioselective acylation (CEA) coupled with LC/MS analysis.…”

Targeting Sphingosine Kinases for the Treatment of Cancer

“…As summarized below, ABC294640 has therapeutic activity in diverse mouse tumor models both alone and in combination with other anticancer drugs (Antoon, White, Driver, Burow, & Beckman, 2012; Antoon et al, 2010; Antoon, White, et al, 2011; Beljanski et al, 2010; Beljanski, Knaak, et al, 2011; Beljanski, Lewis, et al, 2011; Dai et al, 2017; Dai, Smith, Foroozesh, Miele, & Qin, 2018; French et al, 2010; Qin et al, 2014; Schrecengost et al, 2015; Venant et al, 2015; Venkata et al, 2014; Wallington-Beddoe et al, 2014; Xu et al, 2018; Xun et al, 2015; Zhou, Chen, & Yu, 2018), as well as a number of rodent inflammation models (Fitzpatrick, Green, Frauenhoffer, et al, 2011; Fitzpatrick, Green, Maines, & Smith, 2011; Liu et al, 2012; Maines et al, 2008; Maines, Fitzpatrick, Green, Zhuang, & Smith, 2010; Maines et al, 2006; Poti et al, 2012; Shi et al, 2012) not discussed here. Additionally, ABC294640 diminished tumor incidence and multiplicity in the azoxymethane/dextran sulfate sodium model of colon carcinogenesis (Chumanevich et al, 2010).…”

“…However, synergistic cell death was produced with the protea-some inhibitor bortezomib and the multityrosine kinase inhibitor (i.e., Bcr-Abl inhibitor) imatinib when either was combined with ABC294640 (Wallington-Beddoe et al, 2014). ABC294640 treatment of cervical carcinoma cells promoted apoptosis that was amplified by combination with the BCL-2 inhibitor GDC-0199 both in vitro and in vivo (Xu et al, 2018). …”