Antitumor Activity of Sphingosine Kinase Inhibitors

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.

Sphingosine kinase 1 and 2 regulate the capacity of mesangial cells to resist apoptotic stimuli in an opposing manner

“…SK-1 has been attributed a key function in cell proliferation and migration, and upregulation of SK-1 mRNA has been reported for several tumour tissues and cell lines (French et al, 2003;Dö ll et al, 2005Dö ll et al, , 2007Alemany et al, 2007). In line with this, recently developed inhibitors of SK-1 are effective in reducing tumour cell growth in vitro and tumour growth in mice (French et al, 2003(French et al, , 2006). In contrast, SK-2 has been attributed a pro-apoptotic function based on cellular transfection experiments (Liu et al, 2003).…”

Lipid signalling in disease

“…125). To further clarify the mechanism of action of S1P removal, it would be interesting to compare the S1P antibodies with SphK inhibitors, which also have antiproliferative activity 126 , and are also expected to cause a build-up of intracellular sphingosine. An alternative strategy for lowering S1P levels might be the activation of S1P lyase 127 , an ER-localized enzyme, which cleaves S1P to yield ethanolamine phosphate and hexadecanal.…”

Adipocyte Lipolysis-stimulated Interleukin-6 Production Requires Sphingosine Kinase 1 Activity

“…Sphingosine kinase inhibitor 2 (SKI-2, Cayman Chemical), a selective inhibitor of SphK (27), was dissolved in dimethylformamide. SP 600125 and JNK inhibitor VIII were purchased from Cayman Chemical.…”