Sphingosine kinase is a conserved lipid kinase that catalyzes formation sphingosine-1-phosphate, which is a key promotor in cancer. SKI-II is an oral active and synthetic inhibitor of sphingosine kinase (SK) activity, with IC50 values of 78 μM and 45 μM for SK1 and for SK2, respectively. SKI II causes an irreversible inhibition of SK1 by inducing its lysosomal and/or proteasomal degradation. SKI II (1.25 μM, 48 h) in combination with DDP has a clear synergistic effect in human gastric carcinoma SGC7901/DDP cell line[3]. Chronic SKI II (50.0 mg/kg, 3-weekly i.p. for 16 weeks) administration leads to permanent reduction of S1P concentrations in plasma in mice[4]. SKI II (50.0 mg/kg, IP; 100 mg/kg, PO) treatment reduces tumor growth in mice bearing solid tumor model[5].
SKI II 细胞实验
Cell Line
Concentration
Treated Time
Description
References
U3054MG cells
2.66 µM
5 days
Decreased invasion of glioblastoma cell spheroids
BMC Cancer. 2023 Aug 16;23(1):762.
HK-2 cells
5 µM
24 hours
Inhibition of SK1 activity completely abolished the protective effect of hiPSC-MSCs-EVs on H/R-injured HK-2 cells
Cell Death Dis. 2017 Dec 11;8(12):3200.
HeLa
10 µM
24 hours
SKI II treatment significantly increased the levels of dhSM and dhCDH in HeLa cells, indicating inhibition of Des1 activity.
J Lipid Res. 2014 Aug;55(8):1711-20.
T98G
10 µM
24 hours
SKI II treatment significantly increased the levels of dhSM and dhCDH in T98G cells, indicating inhibition of Des1 activity.
J Lipid Res. 2014 Aug;55(8):1711-20.
PC12 cells
10 µM
24 hours
To study the effect of SKI II on PC12 cell viability, results showed that SKI II significantly decreased the viability of PC12 cells.
Neurochem Res. 2014 Apr;39(4):645-52.
CaOV3 ovarian cancer cells
5 µM
24-48 hours
SKI-II significantly enhanced curcumin-induced apoptosis and growth inhibition by facilitating ceramide production, p38 activation and Akt inhibition
Cancer Sci. 2012 Aug;103(8):1538-45.
HGC 27
10 µM
4 hours
SKI II significantly reduced the production of CerC6NBD in HGC 27 cells, indicating inhibition of Des1 activity.
J Lipid Res. 2014 Aug;55(8):1711-20.
1080 GSCs
2.66 µM
4 weeks
Impaired the self-renewal capacity of temozolomide-resistant GSCs
BMC Cancer. 2023 Aug 16;23(1):762.
Rat islet cells
10 or 20 µM
48 hours
To assess the effect of SKI II on oleate-induced β-cell proliferation, results showed that SKI II inhibited oleate-induced β-cell proliferation.
Diabetes. 2022 Jun 1;71(6):1218-1232.
A2780 ovarian cancer cells
5 µM
48 hours
SKI-II synergized with curcumin to inhibit A2780 cell proliferation
Cancer Sci. 2012 Aug;103(8):1538-45.
SKOV3 ovarian cancer cells
5 µM
48 hours
SKI-II synergized with curcumin to inhibit SKOV3 cell proliferation
Cancer Sci. 2012 Aug;103(8):1538-45.
NCH82 cells
2.66 µM
5 days
Synergistically inhibited glioblastoma cell growth and potentiated glioblastoma cell death
BMC Cancer. 2023 Aug 16;23(1):762.
Primary human peripheral blood lymphocytes (PBL)
5 µM
6-24 hours
Reduced phosphorylation of rpS6 and eIF4E, affecting cellular translational capacity
Front Physiol. 2022 Mar 17;13:856143.
HT-29 cells
5 µM
72 hours
Facilitated ABC294640-induced cytotoxicity against HT-29 cells
J Exp Clin Cancer Res. 2015 Sep 4;34(1):94.
SKI II 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6 mice
AOM-induced colon carcinogenesis model
Oral
100 mg/kg
Once a week for 3 weeks
SKI-II significantly reduced the number of ACF per colon induced by AOM
Carcinogenesis. 2017 Dec 7;38(12):1218-1227
Sprague-Dawley rats
Renal ischemia-reperfusion injury model
Subcutaneous injection
50 mg/kg
Single dose 15 min before reperfusion
SK1 inhibition completely abolished the renal protective effect of hiPSC-MSCs-EVs in a rat I/R injury model
Cell Death Dis. 2017 Dec 11;8(12):3200.
Wistar rats
Glucose and lipid emulsion (GLU + CLI) infusion model
Oral gavage
50 mg/kg
Once daily for 72 hours
To assess the effect of SKI II on GLU + CLI-induced β-cell proliferation, results showed a negative correlation between plasma SKI II levels and β-cell proliferation.
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