Fingolimod (FTY720) HCl

Fingolimod (FTY720), an immunosuppressant agent, usually used in the treatment of multiple sclerosis, also has anticancer actions and can act as an HDACi (Histone deacetylase inhibitors)[1].

In vitro, Fingolimod at 7.5 or 10 µM, induced a significant reduction in cell viability in D283 and DAOY cultures, also led to a significant increase in the levels of acetylated H3[1]. In vitro, Fingolimod showed cytotoxic antiproliferative effects against androgen-dependent and -independent prostate cancer cells with IC50 ranging from 3.0 ± 0.3 to 6.8 ± 1.7 µM[2]. Jurkat T-lymphocytes exposure to Fingolimod suppressed the amplitude of delayed-rectifier K+ current (IK(DR)) in a time- and concentration-dependent manner with an IC50 value of 1.51 µM[3]. Fingolimod reduced the proliferation and viability of Ph(+) and Ph(-) ALL cell lines and patient samples with IC 50 values for viability between 5.3 to 7.9 µM[4]. Fingolimod differentially suppressed the viability of the OSCC cell lines SCC4, SCC25, and SCC2095 with IC50 values of 6.1, 6.3, and 4.5 µM, respectively[5].

In vivo, E13 C57BL/6 wildtype mice were treated with 1 mg/kg significantly increased the survival of DCX+ neurons in the DG (dentate gyrus) and the SVZ (the subventricular zone) 4 weeks after irradiation as well as a slight increase of proliferating cells[6]. In vivo, 5xFAD mice were treated with 1 mg/kg/day fingolimod decreased both peripheral blood lymphocyte counts and brain Aβ levels, but treated with 0.03 mg/kg/day improved memory, decreased activation of brain microglia and astrocytes, and restored hippocampal levels of GABA and glycerophosphocholine with no effect on circulating lymphocyte counts[7]. In vivo, C57BL/6JOlaHsd mice were treated with 0.5 mg/kg fingolimod increased lesion size (stroke) but decreased ipsilateral brain atrophy in younger mice, without an effect on behavioural outcomes[8].

References:

[1] Perla AS, et al. Fingolimod (Fingolimod) reduces viability and survival and increases histone H3 acetylation in medulloblastoma cells. Pediatr Hematol Oncol. 2020 Mar;37(2):170-175.

[2] Allam RM, et al. Fingolimod interrupts the cross talk between estrogen metabolism and sphingolipid metabolism within prostate cancer cells. Toxicol Lett. 2018 Jul;291:77-85.

[3] Chang WT, et al. Actions of Fingolimod (Fingolimod), a Sphingosine-1-Phosphate Receptor Modulator, on Delayed-Rectifier K+ Current and Intermediate-Conductance Ca2+-Activated K+ Channel in Jurkat T-Lymphocytes. Molecules. 2020 Oct 2;25(19):4525.

[4] Wallington-Beddoe CT, et al. Fingolimod produces caspase-independent cell death of acute lymphoblastic leukemia cells. Autophagy. 2011 Jul;7(7):707-15.

[5] Bai LY, et al. Fingolimod Induces Autophagy-Associated Apoptosis in Human Oral Squamous Carcinoma Cells, in Part, through a Reactive Oxygen Species/Mcl-1-Dependent Mechanism. Sci Rep. 2017 Jul 17;7(1):5600.

[6] Metzdorf J, et al. Fingolimod for Irradiation-Induced Neurodegeneration. Front Neurosci. 2019 Jul 9;13:699.

[7] Carreras I, et al. Dual dose-dependent effects of fingolimod in a mouse model of Alzheimer's disease. Sci Rep. 2019 Jul 29;9(1):10972.

[8] Diaz Diaz AC, et al. Preclinical Evaluation of Fingolimod in Rodent Models of Stroke With Age or Atherosclerosis as Comorbidities. Front Pharmacol. 2022 Jul 13;13:920449.