Sphingosine kinase inhibitors in the apoptosis of leukaemia cells

Pallis, Monica

doi:10.1016/s0145-2126(01)00148-5

Cited by 6 publications

(7 citation statements)

References 16 publications

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“…71 Because P-glycoprotein expression is among the strongest prognostic factors in acute myologenous leukemia, agents such as DMS, might be useful therapeutically. 72 These results with leukemia specimens that have not been subjected to in vitro selection validate the sphingolipid rheostat regulation of the apoptotic pathway in fresh human tumors, and support initiation of pilot studies and phase I clinical trials that include DMS and other sphingosine kinase inhibitors as part of the regimen.…”

Section: S1p In Hematopoietic Malignancies: Potential Use Of Sphingossupporting

confidence: 56%

Sphingosine 1-phosphate as a therapeutic agent

2002

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The bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P), formed by activation of sphingosine kinase in response to diverse stimuli, is an important lipid mediator that has novel dual actions -both inside and outside of cells. S1P is the ligand for a family of five G protein-coupled receptors. Activation of these GPCRs by S1P or dihydro-S1P regulates diverse processes, including cell migration, angiogenesis, vascular maturation, heart development, and neurite retraction. There is also abundant evidence that S1P can function as a second messenger important for regulation of calcium homeostasis, cell growth, and suppression of apoptosis. In many cases, the intracellular level of S1P and ceramide, another important sphingolipid metabolite associated with cell death and cell growth arrest, coordinately determine cell fate. Changes in S1P and ceramide have been implicated in a number of pathological conditions in which apoptosis plays an important role. Importantly, radiation-induced oocyte loss in adult female mice, the event that drives premature ovarian failure and infertility in female cancer patients, was completely prevented by in vivo therapy with S1P. Understanding the biosynthesis, metabolism and functions of S1P can uncover new targets for the pharmaceutical and therapeutic applications of S1P.

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Section: S1p In Hematopoietic Malignancies: Potential Use Of Sphingossupporting

confidence: 56%

Sphingosine 1-phosphate as a therapeutic agent

2002

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“…33 Actually, F-12509a does not inhibit other lipid kinases nor protein kinase C 33 in contrast to these sphingosine derivatives. [40][41][42] Even though sphingosine derivatives were found equipotent for primary leukemic and drug-resistant leukemia cells, [43][44][45] and capable of inhibiting tumor growth in vivo, they did cause strong hemolysis, [46][47][48] a drawback that is not seen with F-12509a. This latter indeed is not toxic in mice (Calvet C, Cuvillier O, unpublished observations) making F-12509a a good candidate for further studies in animals.…”

Section: Discussionmentioning

confidence: 99%

Overcoming MDR-associated chemoresistance in HL-60 acute myeloid leukemia cells by targeting shingosine kinase-1

et al. 2005

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We examined the involvement of sphingosine kinase-1, a critical regulator of the sphingolipid balance, in susceptibility to antineoplastic agents of either sensitive or multidrugresistant acute myeloid leukemia cells. Contrary to parental HL-60 cells, doxorubicin and etoposide failed to trigger apoptosis in chemoresistant HL-60/Doxo and HL-60/VP16 cells overexpressing MRP1 and MDR1, respectively. Chemosensitive HL-60 cells displayed sphingosine kinase-1 inhibition coupled with ceramide generation. In contrast, chemoresistant HL-60/ Doxo and HL-60/VP16 had sustained sphingosine kinase-1 activity and did not produce ceramide during treatment. Enforced expression of sphingosine kinase-1 in chemosensitive HL-60 cells resulted in marked inhibition of apoptosis that was mediated by blockade of mitochondrial cytochrome c efflux hence suggesting a control of apoptosis at the premitochondrial level. Incubation with cell-permeable ceramide of chemoresistant cells led to a sphingosine kinase-1 inhibition and apoptosis both prevented by sphingosine kinase-1 overexpression. Furthermore, F-12509a, a new sphingosine kinase inhibitor, led to ceramide accumulation, decrease in sphingosine 1-phosphate content and caused apoptosis equally in chemosensitive and chemoresistant cell lines that is inhibited by adding sphingosine 1-phosphate or overexpressing sphingosine kinase-1. F-12509a induced classical apoptosis hallmarks namely nuclear fragmentation, caspase-3 cleavage as well as downregulation of antiapoptotic XIAP, and release of cytochrome c and SMAC/Diablo. Leukemia (2006) 20, 95-102.

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“…Previous studies have suggested that the modulation of sphingolipid metabolic enzyme affects chemosensitivity [28]. Based on these reports, we analyzed how the modulation of SPHK1 affects the daunorubicin (DA) sensitivity of human leukemia cell lines, K562, which is DA-resistant, and NALM-17, which is DA-sensitive.…”

Section: Effects Of Modulation Of Sphk1 On Da-sensitivity Of K562 Celmentioning

confidence: 99%

Implications of sphingosine kinase 1 expression level for the cellular sphingolipid rheostat: relevance as a marker for daunorubicin sensitivity of leukemia cells

et al. 2008

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We recently reported increased sphingosine kinase 1 (SPHK1) and decreased neutral sphingomyelinase 2 (NSMase2) gene expression in myelodysplastic syndromes and acute leukemia. This alteration is supposed to change the cellular sphingolipid metabolites; however, positive correlations were observed between daunorubicin (DA)-IC50 and the SPHK1 message but not between DA-IC50 and NSMase2 messages, when 16 different leukemia cell lines were used to analyze the relationship between gene expressions and chemosensitivity against DA. Using two cell lines with either the highest or lowest SPHK1 expression, cellular ceramides and sphingosine 1-phosphate (S1P) were quantified by liquid chromatography/mass spectrometry. Increased ceramide was observed in DA-sensitive, but not in DA-resistant cell lines treated with low doses of DA. Upon DA treatment, S1P decreased more in the sensitive cell lines than in resistant cell lines. A SPHK inhibitor recovered the DA sensitivity of DA-resistant cells. The modulation of SPHK1 gene expression by either overexpression or using siRNA affected the DA sensitivity of representative cell lines. Results clearly show that SPHK1 is both a good marker to predict the DA sensitivity of leukemia cells and a potential therapeutic target for leukemia with high SPHK1 expression, and suggest that the sphingolipid rheostat plays a significant role in DA-induced cytotoxicity.

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Sphingosine kinase inhibitors in the apoptosis of leukaemia cells

Cited by 6 publications

References 16 publications

Sphingosine 1-phosphate as a therapeutic agent

Sphingosine 1-phosphate as a therapeutic agent

Overcoming MDR-associated chemoresistance in HL-60 acute myeloid leukemia cells by targeting shingosine kinase-1

Implications of sphingosine kinase 1 expression level for the cellular sphingolipid rheostat: relevance as a marker for daunorubicin sensitivity of leukemia cells

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