Background
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].
芬戈莫德(FTY720)是一种免疫抑制剂,通常用于治疗多发性硬化症,也有抗癌作用,可以作为HDACi(组蛋白脱乙酰酶抑制剂)[1]。
在体外,在7.5或10μM时,芬戈莫德诱导D283和DAOY培养物中的细胞活力明显下降,还导致乙酰化H3的水平明显增加[1]。在体外,Fingolimod对雄性激素依赖性和非依赖性前列腺癌细胞显示出细胞毒性抗增殖作用,IC50范围为3.0±0.3至6.8±1.7 μM[2]。Jurkat T淋巴细胞接触Fingolimod后,以时间和浓度依赖的方式抑制延迟整流K+ 电流(IK(DR))的振幅,IC50值为1.51 μM[3]。Fingolimod降低了Ph(+)和Ph(-)ALL细胞系和患者样本的增殖和生存能力,其生存能力的IC50值在5.3至7.9 μM之间[4] 。Fingolimod对OSCC细胞系SCC4、SCC25和SCC2095的生存能力有不同程度的抑制,IC50值分别为6.1、6.3和4.5 μM[5]。
体内试验表明,E13 C57BL/6野生型小鼠在照射4周后,用1 mg/kg的剂量处理,可明显提高DG(齿状回)和SVZ(室下区)中DCX+神经元的存活率,同时增殖细胞也有轻微增加[6]。在体内,5xFAD小鼠接受1 mg/kg/day的芬戈莫德治疗后,外周血淋巴细胞计数和大脑Aβ 水平均下降,但接受0.03 mg/kg/day的治疗后,记忆力得到改善,大脑小胶质细胞和星形胶质细胞的激活减少,海马的GABA和甘油磷酸胆碱水平恢复,对循环淋巴细胞计数没有影响[7]。在体内,C57BL/6JOlaHsd小鼠接受0.5 mg/kg芬戈莫德治疗后,病变大小(中风)增加,但同侧脑萎缩减少,对行为结果没有影响[8]。
参考文献:
[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.
Protocol
| Cell experiment [1]: |
|
Cell lines
|
bone marrow derived macrophages
|
|
Preparation Method
|
BMDMs were stimulated with MSU, GM-CSF/IL-1β or nigericin ± fingolimod (2.5 μM) or febuxostat (200 μM) and UA levels, ROS, XO, and PP2A activities, Xdh (XO) expression and secreted IL-1β levels were determined.
|
|
Reaction Conditions
|
2.5 μM; 3 h
|
|
Applications
|
Fingolimod reduced intracellular and secreted UA (catalyzes uric acid) levels, Xdh expression, XO (Xanthine oxidase) activity, ROS (reactive oxygen species) generation and IL-1β secretion, whereas febuxostat enhanced PP2A (Protein phosphatase 2A) activity.
|
| Animal experiment [2]: |
|
Animal models
|
C57BL6/J mice
|
|
Preparation Method
|
Mechanical force-induced HSs were generated in C57BL6/J mice by suturing a dorsal incision and applying a stretching device on Days 6, 8, 10, and 12. On Days 8, 10, and 12, intracutaneous Fingolimod (10 μM) or control vehicle injections were performed. On Day 14, scar tissues and blood were procured and subjected to histology and flow cytometry.
|
|
Dosage form
|
10 μM; i.c.
|
|
Applications
|
Flow cytometry showed that Fingolimod decreased the frequencies of macrophages with M2 predominance in the scars but had no effect on total, CD4+, or CD8a+ T cell frequencies. Fingolimod also decreased the vascular endothelial cell frequencies in the scar along with the microvessels, as determined by immunohistochemistry. Compared to the vehicles, Fingolimod treatment significantly reduced the gross scar area and the cross-sectional scar area on histology. On the other hand, Fingolimod tended to reduce white blood cells and significantly reduced the lymphocyte frequencies in the blood.
|
|
参考文献:
[1] Elsayed S, et al. Protein phosphatase 2A regulates xanthine oxidase-derived ROS production in macrophages and influx of inflammatory monocytes in a murine gout model. Front Pharmacol. 2022 Nov 17;13:1033520.
[2] Aoki M, et al. The Immunosuppressant Fingolimod (Fingolimod) for the Treatment of Mechanical Force-Induced Abnormal Scars. J Immunol Res. 2020 Jan 7;2020:7057195.
|
没有评价数据