New immunosuppressants with potential implication in multiple sclerosis

Gonsette, R

doi:10.1016/j.jns.2004.04.025

Cited by 26 publications

(21 citation statements)

References 56 publications

(44 reference statements)

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“…1 FTY720 potently inhibits a variety of experimental autoimmune disorders, such as type I diabetes 2 and arthritis, 3 but clinically, its greatest potential for humans appears to be in the prevention of renal graft rejection and treatment of multiple sclerosis (MS) where it is currently in phase 3 clinical trials. 4,5 The immunosuppressive properties of FTY720 stem from its ability to prevent T cells' egress from secondary lymphoid organs and back into circulation, sequestering them away from the transplanted graft, [6][7][8] or preventing their entry into the central nervous system. 9 FTY720 is phosphorylated by sphingosine kinase 2 (SphK2), [10][11][12] and a large body of evidence suggests that the phosphorylated drug (FTY720-P), an analog of sphingosine-1-phosphate (S1P), is the biologically active form.…”

Section: Introductionmentioning

confidence: 99%

The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptors

Payne

Oskeritzian

Griffiths

et al. 2006

Blood

142

101

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FTY720 is a potent immunomodulator drug that inhibits the egress of lymphocytes from secondary lymphoid tissues and thymus. FTY720 is phosphorylated in vivo by sphingosine kinase 2 to FTY720-phosphate, which acts as a potent sphingosine-1-phosphate (S1P) receptor agonist. However, in contrast to S1P, FTY720 has no effect on mast-cell degranulation, yet significantly reduces antigen-induced secretion of PGD 2 and cysteinyl-leukotriene. Unexpectedly, this effect of FTY720 was independent of its phosphorylation and S1P receptor functions. The rate-limiting step in the biosynthesis of all eicosanoids is the phospholipase A 2 (PLA 2 )-mediated release of arachidonic acid from glycerol phospholipids. Although FTY720 also reduced arachidonic acid release in response to antigen, it had no effect on translocation of cPLA 2 or ERK1/2 activation, suggesting that it does not interfere with Fc⑀RI-mediated events leading to cPLA 2 activation. Remarkably, however, FTY720 drastically inhibited recombinant cPLA 2 ␣ activity, whereas FTY720-phosphate, sphingosine, or S1P had no effect. This study has uncovered a unique action of FTY720 as an inhibitor of cPLA 2 ␣ and hence on production of all eicosanoids. Our results have important implications for the potential therapeutic mechanism of action of FTY720 in eicosanoid-driven inflammatory disorders such as asthma and multiple sclerosis. IntroductionFTY720 is a novel immunosuppressive agent that was derived from myriocin, a sphingosine-like fungal metabolite. 1 FTY720 potently inhibits a variety of experimental autoimmune disorders, such as type I diabetes 2 and arthritis, 3 but clinically, its greatest potential for humans appears to be in the prevention of renal graft rejection and treatment of multiple sclerosis (MS) where it is currently in phase 3 clinical trials. 4,5 The immunosuppressive properties of FTY720 stem from its ability to prevent T cells' egress from secondary lymphoid organs and back into circulation, sequestering them away from the transplanted graft, [6][7][8] or preventing their entry into the central nervous system. 9 FTY720 is phosphorylated by sphingosine kinase 2 (SphK2), [10][11][12] and a large body of evidence suggests that the phosphorylated drug (FTY720-P), an analog of sphingosine-1-phosphate (S1P), is the biologically active form. FTY720-P can bind to all of the known S1P receptors, except S1P 2 , 6,13,14 and has been shown to regulate S1P 1 actions that are crucial for lymphocyte migration and trafficking. [15][16][17][18] Nevertheless, the exact mechanism of action of this prodrug is still a matter of debate. [19][20][21] S1P is also an important chemoattractant in the immune system, modulating T-cell responses to chemokines (reviewed in Cyster 13 and Rosen and Goetzl 18 ).FTY720 inhibits airway inflammation, induction of bronchial hyperresponsiveness, and lymphocyte and eosinophil infiltration in an actively Ag-sensitized murine asthma model, 22 suggesting that it might have therapeutic benefits in asthma.Given that S1P and its receptors may pla...

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Section: Introductionmentioning

confidence: 99%

The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptors

Payne

Oskeritzian

Griffiths

et al. 2006

Blood

142

101

View full text Add to dashboard Cite

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“…However, it is plausible that other anthracyclines or related compounds can be identified that can correct ΔF508-CFTR kinesis without toxicity. For example, we are intrigued by the recent clinical development of the anthraquinone pixantrone [51][52][53] for multiple sclerosis. Pixantrone essentially has a heterocyclic ring in place of the A-ring phenyl group of the anthraquinones, resulting in greatly reduced cardiotoxicity and other side effects.…”

Section: Discussionmentioning

confidence: 99%

“…Pixantrone essentially has a heterocyclic ring in place of the A-ring phenyl group of the anthraquinones, resulting in greatly reduced cardiotoxicity and other side effects. Thus, pixantrone is an example where cardiotoxicity (undesirable effect) was separated from myelosuppression (desirable effect) using SAR [51]. A similar project to develop Dox analogs that promote functional expression of ΔF508-CFTR without associated toxicities may provide a clinical benefit in CF.…”

Section: Discussionmentioning

confidence: 99%

Altered Biogenesis of ΔF508-CFTR Following Treatment with Doxorubicin

Maitra¹,

Hamilton²

2007

Cell Physiol Biochem

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Cystic fibrosis (CF) is caused by mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The most common of these mutations is deletion of a phenylalanine residue at position 508 (ΔF508), which accounts for ñ70% of all CF alleles. This mutation interferes with the biogenesis and maturation of ΔF508-CFTR to the plasma membrane. However, ΔF508-CFTR can partially function upon proper localization. Thus, pharmacological correction of ΔF508-CFTR maturation holds promise in CF therapy. Our previous studies indicate that a single non-cytotoxic dose of the anthracycline doxorubicin (Dox) significantly increase ΔF508-CFTR-associated chloride secretion in MDCK cells by increasing the expression of this protein at the apical plasma membrane. We report here that Dox alters the biogenesis of ΔF508-CFTR. Treatment with Dox increases the resistance of ΔF508-CFTR to trypsin digestion, possibly by expediting protein folding. Further, treatment with Dox reduces the amount of polyubiquitinated ΔF508-CFTR in cells and prolongs the half-life of this protein. Concomitantly, treatment with Dox decreases the association of ΔF508-CFTR with HSP70 but does not alter the expression of major HSP70 family members. Based on these results, we propose that Dox expedites the folding and maturation of ΔF508-CFTR by acting as a pharmacological chaperone, which consequently promotes the functional expression of this protein in MDCK cells.

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“…World Health Organization [108], immunosuppressants can be divided into three categories, according to their target: drugs acting on intracellular ligands, cell surface ligands and anti-cytokines.…”

Section: New Approaches To Immunotherapy Of Msmentioning

confidence: 99%

Current Status and Future Prospective of Immunointervention in Multiple Sclerosis

Cavaletti¹

2006

CMC

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Multiple sclerosis (MS) is a complex neurological disorder characterized by inflammation and degeneration of the central nervous system, primarily involving the white matter. On the basis of a wide body of evidence in experimental models and in affected patients, several attempts to treat MS using drugs which modulate immune reactions have been performed or are currently ongoing. However, it should be stressed that inflammation does not have only a detrimental effect in MS. In fact, parts of the inflammatory events are crucial for the control and conclusion of the acute phase of damage and it is probable that they actually favor regeneration and recovery. Due to the above, several trials with immunosuppressant drugs failed or were suspended because of unexpected worsening of the course of MS. The knowledge of MS immunopathogenesis is so rapidly evolving that any attempt to review it is in some way frustrating. On the other hand, this evolution is at the basis of the several new treatment options which can be hypothesized for this disease. The current status of immunosuppression in MS and the possible future development of MS treatment will be reviewed, with particular reference to those treatments which have already been tested in clinical trials and which are based on sound evidence of a putative interference with specific events occurring in MS, with the sparing of general immunity.

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New immunosuppressants with potential implication in multiple sclerosis

Cited by 26 publications

References 56 publications

The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptors

The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptors

Altered Biogenesis of ΔF508-CFTR Following Treatment with Doxorubicin

Current Status and Future Prospective of Immunointervention in Multiple Sclerosis

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