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SKI V is a noncompetitive and potent non-lipid sphingosine kinase (SPHK; SK) inhibitor with an IC50 of 2 μM for GST-hSK. SKI V potently inhibits PI3K with an IC50 of 6 μM for hPI3k. SKI V decreases formation of the mitogenic second messenger sphingosine-1-phosphate (S1P). SKI V induces apoptosis and has antitumor activity[1][2].
SKI V has weak activity toward ERK2 (IC50 of 80 μM for hERK2) and does not inhibit PKC-α[1]. SKI V (10 μM; for 24 hours) inhibits cancer cell proliferation and induces apoptosis[1]. SKI V (0.2, 1, 5 μM; pretreated for 1 hour) decreases phospho-Akt and phospho-MEK levels. Near-confluent cultures of JC cells are serum-starved for 16 hours, followed by pretreatment SKI V for 1 hour[2]. SKI V has IC50s for inhibition of sphingosine kinase (SK) and tumor cell proliferation of ～2 μM[1]. SKI V (20 μg/ml) inhibits not only purified but endogenous SK in in MDA-MB-231 cells[1].SKI V (0.2, 1, 5 μM) inhibits intracellular S1P formation in JC cells in a dose-dependent fashion[2]. Cell Proliferation Assay[1] Cell Line: T24 tumor cells
SKI V (75 mg/kg; i.p.; days 1, 5, 9, 15) significantly lowers tumor growth (>50% decreased at day 18) than control animals[1]. Animal Model: 6-8 weeks old BALB/c female mice with JC mammary adenocarcinoma cells[1]
[1]. French KJ, et al. Discovery and evaluation of inhibitors of human sphingosine kinase. Cancer Res. 2003 Sep 15;63(18):5962-9. [2]. French KJ, et al. Antitumor activity of sphingosine kinase inhibitors. J Pharmacol Exp Ther. 2006 Aug;318(2):596-603.
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