Cell lines

MDA-MB-231 human breast cancer cell line

Preparation Method

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

Reaction Conditions

0.1, 0.5, 1, 5, 10, 25, 50, 100 µM for 24 h

Applications

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..

Animal models

Male Balb/c mice

Preparation Method

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.

Dosage form

5 mg/kg/d for 7 days, infection intravenously

Applications

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

• The FASEB Journal (2019).
• J Anim Sci Biotechno 11.1 (2020): 1-13.
• ACS Omega (2020).
• Toxicol Appl Pharm (2020): 115361.
• Biomed Pharmacother 152 (2022) PMID:35653886

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 IC₅₀of 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].

References:
[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.