2-(3,4-Dihydroxy-benzylidene)-benzofuran-3-one,Sphingosine Kinase Inhibitor V

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].

Signaling Pathways >> Apoptosis >> Apoptosis

Research Areas >> Cancer

Signaling Pathways >> PI3K/Akt/mTOR >> PI3K

Signaling Pathways >> Immunology/Inflammation >> SPHK

IC50: 2 μM (GST-hSK), 6 μM (hPI3k) and 80 μM (ERK2)[1]

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 Concentration: 10 μM Incubation Time: For 24 hours Result: Inhibited cancer cell proliferation. Apoptosis Analysis[1] Cell Line: T24 tumor cells Concentration: 10 μM Incubation Time: For 24 hours Result: Induced apoptosis. Western Blot Analysis[2] Cell Line: JC cells Concentration: 0.2, 1, 5 μM Incubation Time: Pretreated for 1 hour Result: Decreased phospho-Akt and phospho-MEK levels.

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] Dosage: 75 mg/kg Administration: IP; days 1, 5, 9, 15 Result: Tumor growth was significantly lower (>50% decreased at day 18) than tumor growth in control animals.

[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.