Effective cytotoxicity against human leukemias and chemotherapy-resistant leukemia cell lines by N-N-dimethylsphingosine

Jendiroba, David; Klostergaard, Jim; Keyhani, Afsaneh; Pagliaro, Lance C.; Freireich, Emil J.

doi:10.1016/s0145-2126(01)00129-1

Cited by 26 publications

(23 citation statements)

References 49 publications

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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 This latter indeed is not toxic in mice (Calvet C, Cuvillier O, unpublished observations) making F-12509a a good candidate for further studies in animals.…”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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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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“…Indeed, in pilot clinical phase I trials with safingol, which also potentiated the tumor-inhibiting effect of doxorubicin in tumor-bearing animals, it was found that safingol can be given safely with doxorubicin. 70 A recent study showed that DMS was equipotent for primary leukemic and drug-resistant leukemia cells, 71 while a Pglycoprotein-positive HL-60 line was even more sensitive than parental HL-60 cells. 71 Because P-glycoprotein expression is among the strongest prognostic factors in acute myologenous leukemia, agents such as DMS, might be useful therapeutically.…”

Section: S1p In Hematopoietic Malignancies: Potential Use Of Sphingosmentioning

confidence: 99%

“…70 A recent study showed that DMS was equipotent for primary leukemic and drug-resistant leukemia cells, 71 while a Pglycoprotein-positive HL-60 line was even more sensitive than parental HL-60 cells. 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 Sphingosmentioning

confidence: 99%

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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“…Thus, the dynamic balance between ceramide and S1P can be a decisive factor in determining whether or not a cell undergoes apoptosis. Inhibitors of SphK1, such as N,N-dimethylsphingosine and L-threo-dihydrosphingosine, induce apoptosis regardless of multidrug resistance expression (Jendiroba et al, 2002), and may provide a new strategy for the treatment of anticancer drugresistant cancers. Indeed, SphK inhibitors reduce gastric tumor growth (Endo et al, 1991) and mammary adenocarcinoma tumor growth in mice (French et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Sphingosine kinase activity counteracts ceramide-mediated cell death in human melanoma cells: role of Bcl-2 expression

et al. 2005

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While most of the pharmacological therapies for melanoma utilize the apoptotic machinery of the cells, the available therapeutic options are limited due to the ability of melanoma cells to resist programmed cell death. Human melanoma cell lines A-375 and M186 are sensitive to ceramide-and Fas-induced cell death, while Mel-2a and M221 are resistant. We have now found that Mel-2a and M221 cells have a significantly higher ceramide/sphingosine-1-phosphate (S1P) ratio than A-375 and M186 cells. As sphingosine kinase (SphK) type 1 plays a critical role in determining the dynamic balance between the proapoptotic sphingolipid metabolite ceramide and the prosurvival S1P, we examined its role in apoptosis of melanoma cells. Increasing SphK1 expression reduced the sensitivity of A-375 melanoma cells to Fas-and ceramide-mediated apoptosis. Conversely, downregulation of SphK1 with small interfering RNA decreased the resistance of Mel-2a cells to apoptosis. Importantly, overexpression of the prosurvival protein Bcl-2 in A-375 cells markedly stimulated SphK1 expression and activity, while downregulation of Bcl-2 reduced SphK1 expression. This link between Bcl-2 and SphK1 might be an additional clue to chemotherapy resistance of malignant melanoma.

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Effective cytotoxicity against human leukemias and chemotherapy-resistant leukemia cell lines by N-N-dimethylsphingosine

Cited by 26 publications

References 49 publications

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

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

Sphingosine 1-phosphate as a therapeutic agent

Sphingosine kinase activity counteracts ceramide-mediated cell death in human melanoma cells: role of Bcl-2 expression

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