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Received for publication January 13, 2006.
Revised April 20, 2006.
Accepted for publication April 20, 2006.
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, as 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 towards 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 demonstrated 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 MEK and Akt phosphorylation by the SK inhibitors. Importantly, SKI-II, is orally bioavailable, detected in the blood for at least 8 hours, and showed a significant inhibition of tumor growth in mice. These compounds are the first examples of non-lipid selective inhibitors of SK with in vivo antitumor activity, and provide leads for further development of inhibitors of this important molecular target.
Key words:
antitumor, chemotherapy, sphingolipid, sphingosine kinase, sphingosine kinase inhibitors, sphingosine-1-phosphate
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