Sphingolipid-metabolizing enzymes control the dynamic balance of the cellular levels of important bioactive lipids, including the apoptotic compound ceramide and the proliferative compound sphingosine 1-phosphate (S1P). Many growth factors and inflammatory cytokines promote the cleavage of sphingomyelin and ceramide leading to rapid elevation of S1P levels through the action of sphingosine kinases (SK1 and SK2). SK1 and SK2 are overexpressed in a variety of human cancers, making these enzymes potential molecular targets for cancer therapy. We have identified an aryladamantane compound, termed ABC294640 [3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide], that selectively inhibits SK2 activity in vitro, acting as a competitive inhibitor with respect to sphingosine with a K i of 9.8 M, and attenuates S1P formation in intact cells. In tissue culture, ABC294640 suppresses the proliferation of a broad panel of tumor cell lines, and inhibits tumor cell migration concomitant with loss of microfilaments. In vivo, ABC294640 has excellent oral bioavailability, and demonstrates a plasma clearance half-time of 4.5 h in mice. Acute and chronic toxicology studies indicate that ABC294640 induces a transient minor decrease in the hematocrit of rats and mice; however, this normalizes by 28 days of treatment. No other changes in hematology parameters, or gross or microscopic tissue pathology, result from treatment with ABC294640. Oral administration of ABC294640 to mice bearing mammary adenocarcinoma xenografts results in dose-dependent antitumor activity associated with depletion of S1P levels in the tumors and progressive tumor cell apoptosis. Therefore, this newly developed SK2 inhibitor provides an orally available drug candidate for the treatment of cancer and other diseases.Sphingolipids have become a focal point in biological research, with excellent rationale for their manipulation for the treatment of diseases, including cancer (reviewed in Ogretmen, 2006;Cuvillier, 2007; and Huwiler and ZangemeisterWittke, 2007). The parent lipid sphingomyelin is a structural component of cellular membranes, but also serves as the precursor for potent second messengers that have profound cellular effects. Stimulus-induced metabolism of these lipids is critically involved in cancer cell biology and inflammatory diseases; hence, this metabolic pathway offers exciting new molecular targets for drug development.In response to stimuli, including growth factors and inflammatory cytokines, sphingomyelin is enzymatically hydrolyzed to ceramide, which can be further hydrolyzed by the action of ceramidase to produce sphingosine. Ceramide and sphingosine induce apoptosis in cancer cells by mechanisms that remain to be elucidated. Sphingosine is rapidly phosphorylated by sphingosine kinase (SK) to produce sphingosine 1-phosphate (S1P), which is mitogenic and antiapoptotic. Through these conversions, a critical balance, i.e., a ceramide/S1P rheostat, has been hypothesized to determine the fate of the cell (Cuvillier e...
A critical step in the mechanism of action of inflammatory cytokines is the stimulation of sphingolipid metabolism, including activation of sphingosine kinase (SK), which produces the mitogenic and proinflammatory lipid sphingosine 1-phosphate (S1P). We have developed orally bioavailable compounds that effectively inhibit SK activity in vitro in intact cells and in cancer models in vivo. In this study, we assessed the effects of these SK inhibitors on cellular responses to tumor necrosis factor alpha (TNFalpha) and evaluated their efficacy in the dextran sulfate sodium (DSS) model of ulcerative colitis in mice. Using several cell systems, it was shown that the SK inhibitors block the ability of TNFalpha to activate nuclear factor kappa B (NFkappaB), induce expression of adhesion proteins, and promote production of prostaglandin E(2) (PGE(2)). In an acute model of DSS-induced ulcerative colitis, SK inhibitors were equivalent to or more effective than Dipentum in reducing disease progression, colon shortening, and neutrophil infiltration into the colon. The effects of SK inhibitors were associated with decreased colonic levels of inflammatory cytokines TNFalpha, interleukin (IL)-1beta, interferon gamma (IFN)-gamma, IL-6, and reduction of S1P levels. A similar reduction in disease progression was provided by SK inhibitors in a chronic model of ulcerative colitis in which the mice received 3-week-long cycles of DSS interspaced with week-long recovery periods. In the chronic model, immunohistochemistry for SK showed increased expression in DSS-treated mice (compared with water-treated controls) that was reduced by drug treatment. S1P levels were also elevated in the DSS group and significantly reduced by drug treatment. Together, these data indicate that SK is a critical component in inflammation and that inhibitors of this enzyme may be useful in treating inflammatory bowel diseases.
Purpose Sphingosine kinases (SK1 and SK2) regulate tumor growth by generating the mitogenic and pro-inflammatory lipid sphingosine 1-phosphate (S1P). This phase I study investigated the safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of ABC294640, a first-in-class orally-available inhibitor of SK2. Experimental Design Escalating doses of ABC294640 were administered orally to patients with advanced solid tumors in sequential cohorts at the following dose levels: 250 mg qd, 250 mg bid, 500 mg bid and 750 mg bid, continuously in cycles of 28 days. Serial blood samples were obtained to measure ABC294640 concentrations and sphingolipid profiles. Results 22 patients were enrolled, and 21 received ABC294640. The most common drug-related toxicities were nausea, vomiting and fatigue. Among the four patients at 750 mg bid, one had dose-limiting grade 3 nausea and vomiting, and two were unable to complete Cycle 1 due to diverse drug-related toxicities. The 500 mg bid dose level was established as the Recommended Phase II Dose. ABC294640 administration resulted in decreases in S1P levels over the first 12 hours, with return to baseline at 24 hours. The best response was a partial response in a patient with cholangiocarcinoma at 250 mg qd, and stable disease was observed in 6 patients with various solid tumors across dose levels. Conclusions At 500 mg bid, ABC294640 is well tolerated and achieves biologically-relevant plasma concentrations. Changes in plasma sphingolipid levels may provide a useful pharmacodynamic biomarker for ABC294640.
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