Abstract
Sphingosine kinase (SK) is an oncogenic sphingolipid-metabolizing enzyme that catalyzes the formation of the mitogenic second messenger sphingosine-1-phosphate (S1P) at the expense of proapoptotic ceramide. Thus, SK is an attractive target for cancer therapy because blockage of S1P formation leads to inhibition of proliferation, as well as the induction of apoptosis in cancer cells. We have recently identified novel SK inhibitors with nanomolar to low micromolar potencies toward recombinant human SK. This study describes the continuing analysis of these inhibitors through in vitro and in vivo experiments. All three structurally diverse SK inhibitors tested showed antitumor activity in mice without exhibiting toxicity. Blood and tumor inhibitor concentrations exceeded in vitro potency levels. Cell signaling analyses in vitro revealed mixed inhibition of mitogen-activated protein kinase kinase and Akt phosphorylation by the SK inhibitors. Importantly, 4-[4-(4-chloro-phenyl)-thiazol-2-ylamino]-phenol (SKI-II) is orally bioavailable, detected in the blood for at least 8 h, and showed a significant inhibition of tumor growth in mice. These compounds are the first examples of nonlipid selective inhibitors of SK with in vivo antitumor activity and provide leads for further development of inhibitors of this important molecular target.
Footnotes
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This work was supported by National Institutes of Health Grant R43 CA097833.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.101345.
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ABBREVIATIONS: S1P, sphingosine-1-phosphate; SK, sphingosine kinase; Pgp, P-glycoprotein; SKI-II, 4-[4-(4-chloro-phenyl)-thiazol-2-ylamino]-phenol, CAS 312636-16-1; SKI-I, 5-naphthalen-2-yl-2H-pyrazole-3-carboxylic acid (2-hydroxy-naphthalen-1-ylmethylene)-hydrazide, CAS 306301-68-8; SKI-V, 2-(3,4-dihydroxy-benzylidene)-benzofuran-3-one; MEK, mitogen-activated protein kinase kinase; HPLC, high-performance liquid chromatography; DMSO, dimethyl sulfoxide; PBS, phosphate-buffered saline; LY294002, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; BAY 43-9006, 4-(4-(3-(4-chloro-3-trifluoromethylphenyl)ureido)phenoxy)pyridine-2-carboxyllic acid methyamide-4-methylbenzenesulfonate; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase.
- Received January 13, 2006.
- Accepted April 20, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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