In vitroanti-leukaemia activity of sphingosine kinase inhibitor (original) (raw)
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Pharmacological Research, 2003
Whereas some sphingolipids such as sphingoid bases and ceramide can mediate and induce cell killing, other sphingolipids such as sphingosine 1-phosphate promote cell survival or proliferation. The tight equilibrium between the intracellular levels of each of these biomodulators is controlled by the various enzymes that either produce or degrade these lipid molecules. Herein, the effects of sphingoid bases and their derivatives on the regulation of (cancer) cell growth and death are reviewed. In addition, the consequences of pharmacological manipulation of the enzymes that govern sphingoid base metabolism on in vitro and in vivo tumor cell growth are presented. Further development of pharmacological tools aimed at interfering with the metabolism of sphingolipids is expected to provide new avenues in the treatment of cancers as well as other diseases.
Sphingosine Kinase Inhibitors and Cancer: Seeking the Golden Sword of Hercules
Cancer Research, 2011
There is considerable evidence that sphingosine kinases play a key role in cancer progression, which might involve positive selection of cancer cells that have been provided with a survival and growth advantage as a consequence of overexpression of the enzyme. Therefore, inhibitors of sphingosine kinase represent a novel class of compounds that have potential as anticancer agents. Poor inhibitor potency is a major issue that has precluded successful translation of these compounds into the clinic. However, recent discoveries have shown that sphingosine kinase 1 is an allosteric enzyme and that some inhibitors offer improved effectiveness by inducing proteasomal degradation of the enzyme or having nanomolar potency. Herein, we provide a perspective about these recent developments and highlight the importance of translating basic pharmacologic and biochemical findings on sphingosine kinase into new drug discovery programs for treatment of cancer. Cancer Res; 71(21); 6576-82. Ó2011 AACR.
Synthesis and evaluation of sphingoid analogs as inhibitors of sphingosine kinases
Bioorganic & Medicinal Chemistry, 2005
Sphingosine 1-phosphate (S1P), a product of sphingosine kinases (SphK), mediates diverse biological processes such as cell differentiation, proliferation, motility and apoptosis. In an effort to search and identify specific inhibitors of human SphK, the inhibitory effects of synthetic sphingoid analogs on kinase activity were examined.
Sphingosine kinase, sphingosine-1-phosphate, and apoptosis
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2002
The sphingolipid metabolites ceramide (Cer), sphingosine (Sph), and sphingosine-1-phosphate (S1P) play an important role in the regulation of cell proliferation, survival, and cell death. Cer and Sph usually inhibit proliferation and promote apoptosis, while the further metabolite S1P stimulates growth and suppresses apoptosis. Because these metabolites are interconvertible, it has been proposed that it is not the absolute amounts of these metabolites but rather their relative levels that determines cell fate. The relevance of this ''sphingolipid rheostat'' and its role in regulating cell fate has been borne out by work in many labs using many different cell types and experimental manipulations. A central finding of these studies is that Sph kinase (SphK), the enzyme that phosphorylates Sph to form S1P, is a critical regulator of the sphingolipid rheostat, as it not only produces the pro-growth, anti-apoptotic messenger S1P, but also decreases levels of pro-apoptotic Cer and Sph.
Advances in Biological Regulation, 2016
Sphingosine kinase (there are two isoforms, SK1 and SK2) catalyses the formation of sphingosine 1-phosphate (S1P), a bioactive lipid that can be released from cells to activate a family of G protein-coupled receptors, termed S1P 1-5. In addition, S1P can bind to intracellular target proteins, such as HDAC1/2, to induce cell responses. There is increasing evidence of a role for S1P receptors (e.g. S1P 4) and SK1 in cancer, where high expression of these proteins in ER negative breast cancer patient tumours is linked with poor prognosis. Indeed, evidence will be presented here to demonstrate that S1P 4 is functionally linked with SK1 and the oncogene HER2 (ErbB2) to regulate mitogen-activated protein kinase pathways and growth of breast cancer cells. Although much emphasis is placed on SK1 in terms of involvement in oncogenesis, evidence will also be presented for a role of SK2 in both T-cell and B-cell acute lymphoblastic leukemia. In patient TALL lymphoblasts and TALL cell lines, we have demonstrated that SK2 inhibitors promote TALL cell death via autophagy and induce suppression of c-myc and PI3K/AKT pathways. We will also present evidence demonstrating that certain SK inhibitors promote oxidative stress and protein turnover via proteasomal degradative pathways linked with induction of p53-and p21-induced growth Introduction-Formation of the bioactive lipid, sphingosine 1-phosphate (S1P) is catalysed by sphingosine kinase. There are two isoforms of sphingosine kinase (SK1 and SK2) which differ in their subcellular localisations, regulation and functions (Pyne et al., 2009). The S1P formed by these enzymes can either be exported from cells (through transporter proteins e.g. Spns2) and act as a ligand on a family of five S1P-specific G protein coupled receptors (S1P 1-5) (Blaho and Hla, 2014) or can bind to specific intracellular target proteins. For instance S1P formed by nuclear SK2 inhibits HDAC1/2 activity to induce c-fos and p21 expression (Hait et al., 2009). Dephosphorylation of S1P is catalysed by S1P phosphatase and the sphingosine formed is then acylated to ceramide catalysed by ceramide synthase isoforms (Stiban et al., 2010). S1P can also be irreversibly cleaved by S1P lyase to produce (E)-2 hexadecenal and phosphoethanolamine (Degagné et al., 2014). The interconversion of ceramide to sphingosine and S1P has been termed the sphingolipid rheostat (Newton et al., 2015). In this model, shifting the balance toward ceramide induces apoptosis, while predominance of S1P formation promotes cell survival. For instance, ceramide activates protein phosphatase 2A (Dobrowsky et al., 1993), which dephosphorylates phosphorylated AKT (Zhou et al., 1998) and thereby alters BAD/Bcl2 regulation to induce apoptosis (Zundel and Giaccia, 1998). In contrast, S1P promotes cell survival, involving for instance, activation of the extracellular signal regulated kinase-1/2 (ERK-1/2) pathway (Pyne et al., 2009). However, the sphingolipid rheostat exhibits greater complexity, as certain ceramide species regulate processes other than apoptosis, such as autophagy and proliferation. This suggests temporal and spatial regulation, where the functionality of the sphingolipid rheostat is governed by compartmentalised signalling involving, for instance, ceramide synthase isoforms that produce different ceramide species with specific stress-dependent signalling functions that govern a defined cellular outcome e.g. apoptosis versus proliferation. The conversion of S1P to (E)-2 hexadecenal and phosphoethanolamine is also considered an exit point in the
Sphingolipid players in the leukemia arena
Biochimica et Biophysica Acta (BBA) - Biomembranes, 2006
Sphingolipids function as bioactive mediators of different cellular processes, mostly proliferation, survival, differentiation and apoptosis, besides being structural components of cellular membranes. Involvement of sphingolipid metabolism in cancerogenesis was demonstrated in solid tumors as well as in hematological malignancies. Herein, we describe the main biological and clinical aspects of leukemias and summarize data regarding sphingolipids as mediators of apoptosis triggered in response to anti-leukemic agents and synthetic analogs as inducers of cell death as well. We also report the contribution of molecules that modulate sphingolipid metabolism to development of encouraging strategies for leukemia treatment. Finally we address how deregulation of sphingolipid metabolism is associated to occurrence of therapy resistance both in vitro and in vivo. Sphingolipids can be considered promising therapeutic tools alone or in combination with other compounds, as well as valid targets in the attempt to eradicate leukemia and overcome drug resistance.
Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases
Biochimica et Biophysica Acta (BBA) - Biomembranes, 2006
Sphingolipids are ubiquitous components of cell membranes and their metabolites ceramide (Cer), sphingosine (Sph), and sphingosine-1phosphate (S1P) have important physiological functions, including regulation of cell growth and survival. Cer and Sph are associated with growth arrest and apoptosis. Many stress stimuli increase levels of Cer and Sph, whereas suppression of apoptosis is associated with increased intracellular levels of S1P. In addition, extracellular/secreted S1P regulates cellular processes by binding to five specific G protein coupled-receptors (GPCRs). S1P is generated by phosphorylation of Sph catalyzed by two isoforms of sphingosine kinases (SphK), type 1 and type 2, which are critical regulators of the "sphingolipid rheostat", producing pro-survival S1P and decreasing levels of pro-apoptotic Sph. Since sphingolipid metabolism is often dysregulated in many diseases, targeting SphKs is potentially clinically relevant. Here we review the growing recent literature on the regulation and the roles of SphKs and S1P in apoptosis and diseases.
SphK1 and SphK2, Sphingosine Kinase Isoenzymes with Opposing Functions in Sphingolipid Metabolism
Journal of Biological Chemistry, 2005
The potent sphingolipid metabolite sphingosine-1-phosphate (S1P) is produced by phosphorylation of sphingosine catalyzed by sphingosine kinase (SphK) types 1 and 2. In contrast to pro-survival SphK1, the putative BH3only protein SphK2 inhibits cell growth and enhances apoptosis. Here we show that SphK2 catalytic activity also contributes to its ability to induce apoptosis. Overexpressed SphK2 also increased cytosolic free calcium induced by serum starvation. Transfer of calcium to mitochondria was required for SphK2induced apoptosis, as cell death and cytochrome c release was abrogated by inhibition of the mitochondrial Ca 2+ transporter. Serum-starvation increased the proportion of SphK2 in the ER and targeting SphK1 to the ER converted it from anti-apoptotic to pro-apoptotic. Overexpression of SphK2 increased incorporation of [ 3 H]palmitate, a s u b s t r a t e f o r b o t h s e r i n e palmitoyltransferase and ceramide synthase, into C16-ceramide, whereas SphK1 decreased it. ESI-MS/MS also revealed an opposite effect on ceramide mass levels. Importantly, specific downregulation of SphK2 reduced conversion of sphingosine to ceramide in the recycling pathway and conversely, downregulation of SphK1 increased it. Our results demonstrate that SphK1 and SphK2 have opposing roles in the regulation of ceramide biosynthesis and suggest that the location of S1P production dictates its functions.
Haematologica, 2017
Sphingosine kinase 1 participates in the activation, proliferation and survival of chronic lymphocytic leukemia cells Sphingosine kinases (SKs) have received the most attention as important enzymes in cancer biology. They participate in the regulation of bioactive sphingolipid metabolism by producing sphingosine-1 phosphate (S1P) which mediates several biological functions, including cell growth, differentiation, cell survival, migration, and angiogenesis among other tasks. 1 S1P generation depends