Background
SB 203580 is a specific inhibitor of p38-MAPK (Mitogen-activated Protein Kinase) pathway [1,2]. SB 203580 inhibits p38 kinase in a manner competitive with ATP with a Ki of 21 nm [2].
SB 203580 inhibit the proliferation of human breast cancer cell line MDA-MB-231 with the IC50 value of was 85.1 μM [3]. SB 203580 inhibited IL-10 production by monocytic WEHI 274.3 cells expressing WT-p38α MAPK in a dose-dependent manner with greater than 95% inhibition at 5 μm and with an IC50 of 0.1μM [4]. IL-2-induced proliferation of primary human T cells, murine CT6 T cells, or BAF F7 B cells is prevented by the p38 MAP kinase inhibitor SB 203580 with an IC50 of 3-5μM [5].
SB-203580 demonstrated moderate to high clearance in all species tested in vivo, with non-linear elimination observed in the rat at plasma concentrations > 1000ng ml -1. Although good solution bioavailability was observed in non-rodents (78% in dog, 32% in monkey), lower and more variable bioavailability was observed in the rat and mouse (3-48%) [6]. SB 203580 treatment significantly improve the white blood cell (WBC) and platelet counts decreased significantly in the DENV-infected mice, suggesting leucopenia and thrombocytopenia, respectively [7].
SB 203580是p38-MAPK（有丝分裂原活化蛋白激酶）通路的特异性抑制剂。它以与ATP竞争的方式抑制p38激酶，Ki值为21纳摩尔。
SB 203580可以抑制人乳腺癌细胞系MDA-MB-231的增殖，其IC50值为85.1微米[3]。在表达WT-p38α MAPK的单核WEHI 274.3细胞中，SB 203580以剂量依赖方式抑制IL-10的产生，在5微米时可达到95%以上的抑制率，并且其IC50为0.1微米[4]。 SB 203580是p38 MAP激酶抑制剂，可以防止IL-2诱导的原代人T细胞、小鼠CT6 T细胞或BAF F7 B细胞增殖，其IC50为3-5μM [5]。
在所有测试的物种中，SB-203580在体内表现出中等到高度的清除能力，在大鼠血浆浓度>1000ng ml -1时观察到非线性消除。尽管非啮齿动物（狗78％，猴子32％）观察到良好的溶液生物利用度，但在大鼠和小鼠中观察到较低且更为不稳定的生物利用度（3-48%）[6]。 SB 203580治疗显着改善了DENV感染小鼠的白细胞计数和血小板计数明显下降，分别提示粒细胞减少和血小板减少[7]。
参考文献:
[1]. Barancik M, Bohacova V, Kvackajova J, Hudecova S, Krizanova O, Breier A: SB 203580, a specific inhibitor of p38-MAPK pathway, is a new reversal agent of P-glycoprotein-mediated multidrug resistance. Eur J Pharm Sci. 2001, 14: 29-36. 10.1016/S0928-0987(01)00139-7.
[2]. Peter R. Young, Megan M. McLaughlin, Sanjay Kumar, et al. Pyridinyl Imidazole Inhibitors of p38 Mitogen-activated Protein Kinase Bind in the ATP Site. The Journal of Biological Chemistry, 1997, 272(18): 12116-12121.
[3]. Duzgun SA, Yerlikaya A, Zeren S, Bayhan Z, Okur E, Boyaci I. Differential effects of p38 MAP kinase inhibitors SB 203580 and SB202190 on growth and migration of human MDA-MB-231 cancer cell line. Cytotechnology. 2017;69(4):711-24.
[4]. Guo, X., R.E. Gerl, and J.W. Schrader. 2003. Defining the involvement of p38alpha MAPK in the production of anti- and proinflammatory cytokines using an SB 203580-resistant form of the kinase. J. Biol. Chem. 278:22237-22242.
[5]. Lali, F. V., Hunt, A. E., Turner, S. J., and Foxwell, B. M. The pyridinyl imidazole inhibitor SB 203580 blocks phosphoinositide-dependent protein kinase activity, protein kinase B phosphorylation, and retinoblastoma hyperphosphorylation in interleukin-2-stimulated T cells independently of p38 mitogen-activated protein kinase. J. Biol. Chem.,275: 7395-7402,?2000
[6]. Ward KW, Prokscht JW, Azzaranot LM, et al. Preclinical pharmacokinetics of SB-203580, a potent inhibitor of p38 mitogen-activated protein kinase. Xenobiotica 2001; 31: 783-97
[7]. Sreekanth GP, Chuncharunee A, Sirimontaporn A, Panaampon J, Noisakran S, Yenchitsomanus PT, et al. SB 203580 modulates p38 MAPK signaling and Dengue virus-induced liver injury by reducing MAPKAPK2, HSP27, and ATF2 phosphorylation. PLoS One. 2016;11:e0149486.
Protocol
| Cell experiment [1]: |
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Cell lines
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MDA-MB-231 human breast cancer cell line
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Preparation Method
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Cells were treated at the logarithmic phase of the growth with various doses of SB 203580 (0.1, 0.5, 1, 5, 10, 25, 50, 100 μM) for 24 h
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Reaction Conditions
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0.1, 0.5, 1, 5, 10, 25, 50, 100 μM for 24 h
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Applications
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SB 203580 did not cause significant cytotoxicity on human MDA-MB-231 breast cancer cell line at low concentrations (0.1-10 μM) as compared to vehicle-treated (0.5% DMSO) control cells. However, the cytotoxic effects of both inhibitors were observed with higher concentrations of 25, 50 and 100 μM..
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| Animal experiment [2]: |
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Animal models
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Male Balb/c mice
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Preparation Method
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Treatments with 2% DMSO alone or SB 203580 dissolved in 2% DMSO were given 1 h before and 1 h and 24 h after DENV infection intravenously. The volume of all injections was 0.4 ml. At 7 days after infection, the mice were euthanized with an overdose intraperitoneal injection of sodium pentobarbital anesthesia.
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Dosage form
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5 mg/kg/d for 7 days, infection intravenously
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Applications
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After the DENV-infected mice were treated with SB 203580, their liver AST levels were significantly reduced, but the changes in ALT were failed to reach statistical significance
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参考文献:
[1]: Duzgun SA, Yerlikaya A, Zeren S, Bayhan Z, Okur E, Boyaci I. Differential effects of p38 MAP kinase inhibitors SB 203580 and SB202190 on growth and migration of human MDA-MB-231 cancer cell line. Cytotechnology. 2017;69(4):711-24.
[2]: Sreekanth GP, Chuncharunee A, Sirimontaporn A, Panaampon J, Noisakran S, Yenchitsomanus PT, et al. SB 203580 modulates p38 MAPK signaling and Dengue virus-induced liver injury by reducing MAPKAPK2, HSP27, and ATF2 phosphorylation. PLoS One. 2016;11:e0149486.
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