scholarly journals More than Just an Immunosuppressant: The Emerging Role of FTY720 as a Novel Inducer of ROS and Apoptosis

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Teruaki Takasaki ◽  
Kanako Hagihara ◽  
Ryosuke Satoh ◽  
Reiko Sugiura
Keyword(s):  
Cancer Treatment ◽  
Defense Mechanisms ◽  
Chemotherapeutic Agents ◽  
Future Directions ◽  
Receptor Modulator ◽  
Cystine Transporter ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor ◽  
Fingolimod Hydrochloride

Fingolimod hydrochloride (FTY720) is a first-in-class of sphingosine-1-phosphate (S1P) receptor modulator approved to treat multiple sclerosis by its phosphorylated form (FTY720-P). Recently, a novel role of FTY720 as a potential anticancer drug has emerged. One of the anticancer mechanisms of FTY720 involves the induction of reactive oxygen species (ROS) and subsequent apoptosis, which is largely independent of its property as an S1P modulator. ROS have been considered as a double-edged sword in tumor initiation/progression. Intriguingly, prooxidant therapies have attracted much attention due to its efficacy in cancer treatment. These strategies include diverse chemotherapeutic agents and molecular targeted drugs such as sulfasalazine which inhibits the CD44v-xCT (cystine transporter) axis. In this review, we introduce our recent discoveries using a chemical genomics approach to uncover a signaling network relevant to FTY720-mediated ROS signaling and apoptosis, thereby proposing new potential targets for combination therapy as a means to enhance the antitumor efficacy of FTY720 as a ROS generator. We extend our knowledge by summarizing various measures targeting the vulnerability of cancer cells’ defense mechanisms against oxidative stress. Future directions that may lead to the best use of FTY720 and ROS-targeted strategies as a promising cancer treatment are also discussed.

Role of Sphingosine 1-Phosphate (S1P) Receptor 1 in Experimental Autoimmune Encephalomyelitis —II

2013 ◽  
Vol 04 (08) ◽  
pp. 638-646 ◽  
Author(s):  
Noriyasu Seki ◽  
Hirotoshi Kataoka ◽  
Kunio Sugahara ◽  
Atsushi Fukunari ◽  
Kenji Chiba
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Autoimmune Encephalomyelitis ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor ◽  
Experimental Autoimmune

The Role of Sphingosine-1-Phosphate (S1P) in Thrombopoiesis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. SCI-54-SCI-54
Author(s):  
Steffen Massberg
Keyword(s):  
Conflicts Of Interest ◽  
Multiphoton Microscopy ◽  
Lipid Mediator ◽  
Severe Thrombocytopenia ◽  
Time Loss ◽  
Sphingosine Kinase 2 ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor

Abstract Human megakaryocytes (MKs) release trillions of platelets each day into the circulation to maintain normal homeostatic platelet levels. However, the signals that control platelet biogenesis in vivo remain incompletely understood. We have recently identified that extracellular sphingosine 1-phosphate (S1P) plays a key role in thrombopoiesis. Using conditional mutants and intravital multiphoton microscopy, we demonstrate that the lipid mediator S1P serves as a critical directional cue guiding the elongation of megakaryocytic proplatelet (PP) extensions from the interstitium into bone marrow sinusoids and triggering the subsequent shedding of PPs into the blood. Correspondingly, mice lacking the S1P receptor S1pr1 develop severe thrombocytopenia caused by both formation of aberrant extravascular PPs and defective intravascular PP shedding. In contrast, activation of S1pr1 signaling leads to the prompt release of new platelets into the circulating blood. In addition to its role as an extracellular mediator, S1P can also function as a second messenger within the intracellular compartment. Correspondingly, we have demonstrated that MKs express the S1P-generating enzyme sphingosine kinase 2 (Sphk2). Sphk2 predominantly localizes to the nucleus and is the major source of intracellular S1P in MKs. Loss of Sphk2 significantly reduced intracellular S1P in MKs and downregulated the expression and activity of Src family kinases (SFKs). At the same time, loss of Sphk2 and inhibition of SFK activity resulted in defective intravascular PP shedding, the final stage of thrombopoiesis. Correspondingly, mice lacking Sphk2 in the hematopoietic system display thrombocytopenia. Collectively, our findings uncover a novel function of S1P as master regulator of efficient thrombopoiesis and might raise new therapeutic options for patients with thrombocytopenia. Disclosures No relevant conflicts of interest to declare.

scholarly journals A novel role of sphingosine 1-phosphate receptor S1pr1 in mouse thrombopoiesis

2012 ◽  
Vol 209 (12) ◽  
pp. 2165-2181 ◽  
Author(s):  
Lin Zhang ◽  
Martin Orban ◽  
Michael Lorenz ◽  
Verena Barocke ◽  
Daniel Braun ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Multiphoton Microscopy ◽  
Therapeutic Options ◽  
Lipid Mediator ◽  
Severe Thrombocytopenia ◽  
Master Regulator ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor

Millions of platelets are produced each hour by bone marrow (BM) megakaryocytes (MKs). MKs extend transendothelial proplatelet (PP) extensions into BM sinusoids and shed new platelets into the blood. The mechanisms that control platelet generation remain incompletely understood. Using conditional mutants and intravital multiphoton microscopy, we show here that the lipid mediator sphingosine 1-phosphate (S1P) serves as a critical directional cue guiding the elongation of megakaryocytic PP extensions from the interstitium into BM sinusoids and triggering the subsequent shedding of PPs into the blood. Correspondingly, mice lacking the S1P receptor S1pr1 develop severe thrombocytopenia caused by both formation of aberrant extravascular PPs and defective intravascular PP shedding. In contrast, activation of S1pr1 signaling leads to the prompt release of new platelets into the circulating blood. Collectively, our findings uncover a novel function of the S1P–S1pr1 axis as master regulator of efficient thrombopoiesis and might raise new therapeutic options for patients with thrombocytopenia.

scholarly journals FTY720 requires vitamin B12-TCN2-CD320 signaling in astrocytes to reduce disease in an animal model of multiple sclerosis

2022 ◽  
Author(s):  
Deepa Jonnalagadda ◽  
Yasuyuki Kihara ◽  
Aran Groves ◽  
Manisha Ray ◽  
Arjun Saha ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Metabolic Pathways ◽  
Type I ◽  
Rna Seq ◽  
Autoimmune Encephalomyelitis ◽  
Altered Expression ◽  
Receptor Modulator ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
S1p Receptor

FTY720 (fingolimod) is a sphingosine 1-phosphate (S1P) receptor modulator and sphingosine analogue approved for multiple sclerosis (MS) therapy, which can functionally antagonize the S1P receptor, S1P1. Vitamin B12 (B12) deficiency produces neurological manifestations resembling MS. Here, we report a new mechanism where FTY720 suppresses neuroinflammation by regulating B12 metabolic pathways. Nuclear RNA-seq of c-Fos-activated astrocytes (called ieAstrocytes) from experimental autoimmune encephalomyelitis (EAE) spinal cords identified up-regulation of CD320, a transcobalamin 2 (TCN2)-B12 receptor, by S1P1 inhibition. CD320 was reduced in MS plaques. Deficiency of CD320 or dietary B12 worsened EAE and eliminated FTY720 efficacy, while concomitantly down-regulating type I interferon signaling. TCN2 functioned as a chaperone for FTY720 and sphingosine, which induced astrocytic CD320 internalization. An accompanying paper identified a requirement for astrocyte sphingosine kinases in FTY720 efficacy and its altered expression in MS brains, molecularly linking MS and B12 deficiency that can be accessed by sphingolipid/fingolimod metabolic pathways.

scholarly journals Role of Sphingosine 1-Phosphate (S1P) Receptor 1 in Experimental Autoimmune Encephalomyelitis —I

2013 ◽  
Vol 04 (08) ◽  
pp. 628-637 ◽  
Author(s):  
Noriyasu Seki ◽  
Yasuhiro Maeda ◽  
Hirotoshi Kataoka ◽  
Kunio Sugahara ◽  
Kenji Chiba
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Autoimmune Encephalomyelitis ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor ◽  
Experimental Autoimmune

Ozanimod for the treatment of relapsing forms of multiple sclerosis

2021 ◽  
Author(s):  
Andrea M Kuczynski ◽  
Jiwon Oh
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Side Effects ◽  
Receptor Subtypes ◽  
Efficacy And Safety ◽  
S1p Receptors ◽  
Receptor Modulator ◽  
Wide Range ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor

Multiple sclerosis (MS) is an inflammatory disease that causes chronic neurological disability in young adults. Modulation of sphingosine 1-phosphate (S1P) receptors, a group of receptors that, among other things, regulate egression of lymphocytes from lymph nodes, has proven to be effective in treating relapsing MS. Fingolimod, the first oral S1P receptor modulator, has demonstrated potent efficacy and tolerability, but can cause undesirable side effects due to its interaction with a wide range of S1P receptor subtypes. This review will focus on ozanimod, a more selective S1P receptor modulator, which has recently received approval for relapsing MS. We summarize ozanimod’s mechanism of action, and efficacy and safety from clinical trials that demonstrate its utility as another treatment option for relapsing MS.

Building a better sphingosine kinase-1 inhibitor

2012 ◽  
Vol 444 (1) ◽  
pp. e1-e2 ◽  
Author(s):  
Kevin R. Lynch
Keyword(s):  
Cancer Progression ◽  
Therapeutic Strategy ◽  
Therapeutic Benefit ◽  
Biochemical Journal ◽  
Molecule Inhibitor ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
S1p Receptor ◽  
Multiple Sclerosis Patients

Sphingosine 1-phosphate (S1P) is currently one of the most intensely studied lipid mediators. Interest in S1P has been propelled by the development of fingolimod, an S1P receptor agonist prodrug, which revealed both a theretofore unsuspected role of S1P in lymphocyte trafficking and that such modulation of the immune system achieves therapeutic benefit in multiple sclerosis patients. S1P is synthesized from sphingosine by two SphKs (sphingosine kinases) (SphK1 and SphK2). Manipulation of SphK levels using molecular biology and mouse genetic tools has implicated these enzymes, particularly SphK1, in a variety of pathological processes such as fibrosis, inflammation and cancer progression. The results of such studies have spurred interest in SphK1 as a drug target. In this issue of the Biochemical Journal, Schnute et al. describe a small molecule inhibitor of SphK1 that is both potent and selective. Such chemical tools are essential to learn whether targeting S1P signalling at the level of synthesis is a viable therapeutic strategy.

scholarly journals A Sphingosine-1-Phosphate Receptor Modulator Attenuated Secondary Brain Injury and Improved Neurological Functions of Mice after ICH

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
T. Bobinger ◽  
T. Bäuerle ◽  
L. Seyler ◽  
S. v Horsten ◽  
S. Schwab ◽  
...  
Keyword(s):  
Brain Injury ◽  
Acute Stage ◽  
Secondary Brain Injury ◽  
Protective Effects ◽  
Receptor Modulator ◽  
Receptor Modulation ◽  
Short Term Study ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor ◽  
The Brain

Background. Stroke activates the immune system and induces brain infiltration by immune cells, aggravating brain injury. Poststroke immunomodulation via (S1P-)receptor modulation is beneficial; however, the S1P-modulator in clinical use (FTY-720) is unspecific, and undesirable side effects have been reported. Previously, we tested effects of a novel selective S1P-receptor modulator, Siponimod, on ICH-induced brain injury in acute stage of the disease. In the current study, we investigated whether protective effects of Siponimod, evaluated in a short-term study, will protect the brain of ICH animals at long term as well. Methods. 134 C57BL/6N mice were divided into sham and ICH-operated groups. Collagenase model of ICH was employed. ICH animals were divided into Siponimod treated and nontreated. Dose- and time-dependent effects of Siponimod were investigated. Contraplay between development of brain injury and the number of lymphocytes infiltrating the brain was investigated by forelimb placing, T-Maze test, brain water content calculation, MRI scanning, and immunostaining. Results. Depending on the therapeutic strategy, Siponimod attenuated the development of brain edema, decreased ICH-induced ventriculomegaly and improved neurological functions of animals after ICH. It was associated with less lymphocytes in the brain of ICH animals. Conclusion. Siponimod is able to decrease the brain injury and improves neurological functions of animals after ICH.

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