Interestingly, a recent study suggested that FTY-720 functions not only by inducing S1PR1 internalization but also by inhibiting ceramide synthases, thereby decreasing cellular levels of ceramides, sphingosine, and pro-inflammatory S1P, while increasing levels of dihydrosphingosine and dihydro-S1P, effects reminiscent to those of the classical ceramide synthase inhibitor fumonisin B1 (Berdyshev et al., 2009). by downregulation of S1PR1, has become the platinum standard for S1P-centric drugs. Here, we review S1P biology and signaling with an emphasis on potential therapeutic benefits of specific interventions and discuss recent development of small molecule antagonists and agonists that target specific subtypes of S1P receptors as well as inhibitors of SphKs. applicability of ABC294640 has been explored in a murine model of breast cancer in which it attenuated the tumor growth in a dose-dependent manner while exhibiting BF 227 a good pharmacological profile, low toxicity, and high target tissue specificity. Reduction in tumor size was correlated with S1P depletion and progressive tumor cell apoptosis (French et al, 2010). Moreover, co-treatment with sorafenib, a tyrosine protein kinase inhibitor approved for use in renal and hepatic malignancy, revealed a synergistic anti-tumor effect (Beljanski et al., 2011). Interestingly, subsequent studies of ABC294640 have exhibited effects of this molecule that go beyond the scope of SphK2 inhibition. Surprisingly, ABC294640 has been recently identified as a partial agonist of the estrogen receptor (ER), attenuating ER-mediated transcription of proliferation-stimulating genes and reducing tumor size in a manner BF 227 similar to that of the current anti-cancer drug tamoxifen (Antoon et al., 2010) These findings raise the possibility that ABC294640 could prove useful in the treatment of ER-sensitive breast cancer. The emerging off-target effects of ABC294640 may in part explain how this seemingly specific SphK2 inhibitor exhibits efficacy for treatment of mice bearing a variety of types of xenografts despite the fact that SphK2 is not the major isoenzyme responsible for cellular S1P synthesis. 3.2 Multiple sclerosis As mentioned above, FTY-720 was recently approved by the FDA for the treatment of multiple sclerosis, an inflammatory autoimmune disorder causing demyelination and scarring in the brain and spinal cord. FTY-720 is usually a sphingosine analogue that is phosphorylated by SphK2 to BF 227 generate a S1P mimetic that is able to bind to all of the S1PRs except S1PR2. With respect to treatment of multiple sclerosis, its most important action is believed to be the internalization of lymphocytic S1PR1 and its degradation, leading to prolonged attenuation of the ability of lymphocytes to sense the S1P gradient between TSPAN17 the circulation and tissues, which is required for their egress from lymph nodes and lymphoid organs. The sequestration prevents autoreactive T cells from infiltrating the nervous system where they BF 227 play an important role in the progression of this disease (Mehling et al., 2008). However, Phase II clinical trials of FTY-720 revealed that its peak effectiveness for multiple sclerosis treatment occurs at doses that are suboptimal for lymphopenia induction (Graler, 2010). This unexpected result, together with the finding that S1P receptors are expressed in several types of neuronal cells (Graler, 2010), suggests that FTY-720 could also exert direct neuroprotective effects in the brain. Indeed, a recent study reported that FTY-720 may be able to reduce astrogliosis via the downregulation of S1PR1 in astrocytes (Brinkmann, 2009), and subsequent work in a mouse model of multiple sclerosis exhibited that the protective effect of FTY-720 was dependent upon astrocytic S1PR1 expression (Choi et al., 2011). In the mean time, it is becoming clear that this functions of S1P in the nervous system are more complex than previously comprehended. For example, it was recently discovered that S1P is an essential player in the development of long-term potentiation in the CA3 region of the hippocampus, establishing a connection for the first time between S1P and memory (Kanno et al., 2010). Increasing understanding of the importance of S1P in the CNS and the multiple actions of FTY-720 and BF 227 other drugs targeting sphingosine kinases suggests this approach deserves concern for treatment of other neurodegenerative diseases. 3.3 Asthma Asthma is a common chronic inflammatory disease characterized by hypercontraction of airway easy muscle cells in response to inhaled or ingested antigens, accompanied by influx of inflammatory cells to the lungs. Specific functions for S1P have been recognized in the hallmark features of this condition. Antigen crosslinking of the high affinity IgE receptor (FcRI) on mast cells induces degranulation, which results in the release of many inflammatory mediators, as well as their migration. Both depend upon stimulation of.
