Abstract
Fingolimod is a well known immunomodulator used by oral route in relapsing multiple sclerosis patients. Upon phosphorylation by sphingosine kinase 2 (SPHK2), fingolimod binds to one or more of at least five G protein coupled receptors known as S1PR1-5, thus it causes S1PRs internalization and consequent sequestration of lymphocytes in lymphoid organs. Fingolimod also affects other signaling pathways. In particular, this drug is able to activate the serine-threonine protein phosphatase 2A (PP2A) which regulates multiple cell signaling cascades by virtue of its phosphatase activity. PP2A loss-of-function may represent one of the major events contributing to cancer development and progression. Hence, there is a need for therapeutic PP2A reactivation. In this regard, fingolimod is revealing a promising candidate for cancer treatment due to its ability to reactivate PP2A, reduce cell viability and promote apoptosis. However, the appropriate dosage and safety remain a challenge.
Highlights
Fingolimod (FTY720), a myriocin analogue structurally related to sphingosine, is a well known immunomodulator, currently used by oral route in relapsing multiple sclerosis patients [1,2]
Upon phosphorylation by sphingosine kinase 2 (SPHK2), fingolimod binds to one or more of at least five G protein coupled receptors known as S1PR1-5, it causes S1PRs internalization and consequent sequestration of lymphocytes in lymphoid organs
The main side effects reported in MS patients treated with higher doses of fingolimod can be ascribed to immunosuppression [46,47]
Summary
Fingolimod (FTY720), a myriocin analogue structurally related to sphingosine, is a well known immunomodulator, currently used by oral route in relapsing multiple sclerosis patients [1,2]. Upon phosphorylation by sphingosine kinase 2 (SPHK2), fingolimod binds to one or more of at least five G protein coupled receptors known as S1PR1-5. S1PR1 couples to Gi to activate Ras/ERK and PI3-kinase/ Akt pathways leading to mitogenic and survival signaling as well as cell migration [3]. S1PR2 couples with multiple heterotrimeric G proteins, including G12/13 which exerts a potent inhibitory effect on Rac GTPase with consequent inhibition of cell migration [3]. Fingolimod exerts the immunosuppressive effects by modulating S1PRs signaling, leading to sequestration of lymphocytes in lymphoid organs, it affects other signaling pathways.
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