CXCR2 is expressed in human neutrophilsand a subset of T-cells, which can mediate neutrophil migration to sites of inflammation through binding with and internalization through its ligand IL-8 or related chemokines containing a common amino-terminal ELR amino acid sequence (Glu-Leu-Arg), such as GROα, GROβ, GROγ, NAP-2 and ENA-78. SB 225002 is a non-peptide, potent and selective CXCR2 inhibitor with IC50 value of 22 nM, >150-fold selectivity over CXCR1 and four other 7-TMRs tested. SB-225002 can produce a dose-dependent inhibition of calcium mobilization induced by IL-8 and GROα with IC50 values of 8 nM and 10 nM, respectively, in differentiated HL60 cells with predominantly express CXCR2 (80%) with a much smaller number of CXCR1 (20%) receptors, as well as inhibit both IL-8 (1nM)- and GROα (10nM)-mediated human neutrophil chemotaxis with IC50s of 20 nM and 60 nM, respectively. This effect of SB-225002 on chemotaxis can also be observed in in vivo study[1]. Daily intraperitoneal injection with SB225002 at dose of 5 mg/kg for 4 weeks showed significantly tumor growth inhibition by ~45% decrease in tumor size of LLC tumor bearing GRK6-/- mice.
作用机制
SB-225002 can inhibit CXCR2 through competition with IL-8.[1]
SB225002 细胞实验
Cell Line
Concentration
Treated Time
Description
References
bone marrow-derived MDSCs
2 μM
4 days
to eliminate the effect of CXCL1 on the generation of MDSCs
Acta Pharm Sin B. 2023 Dec;13(12):4733-4747.
U937-derived macrophages
1 µM
12 h
To evaluate the effect of SB225002 on macrophage invasiveness, results showed that SB225002 significantly inhibited MTD-CAFs-induced macrophage invasion.
J Exp Med. 2016 Dec 12;213(13):2967-2988.
BC-011 carcinoma cells
1 µM
5 days
To evaluate the effect of SB225002 on the proportion of CD44+CD24low/− TICs, results showed that SB225002 significantly reduced the MTD-CAFs-induced increase in CD44+CD24low/− TICs.
J Exp Med. 2016 Dec 12;213(13):2967-2988.
BM-MSCs
200 nM
24 h
SB225002 was used to inhibit the GRO-α receptor, reducing the migration of BM-MSCs towards OS cells.
Mol Oncol. 2018 May;12(5):659-676.
HOS cells
200 nM
24 h
SB225002 was used to inhibit the GRO-α receptor, reducing the invasion and transendothelial migration of HOS cells.
Mol Oncol. 2018 May;12(5):659-676.
C4-2B
50 nM
30 min
To investigate the effect of SB225002 on the migration of C4-2B cells, results showed that SB225002 had no significant effect on the migration of C4-2B cells
Int J Mol Sci. 2021 Feb 17;22(4):1994.
PC-3
50 nM
30 min
To investigate the effect of SB225002 on the migration of PC-3 cells, results showed that SB225002 had no significant effect on the migration of PC-3 cells
Int J Mol Sci. 2021 Feb 17;22(4):1994.
SB225002 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Experimental Autoimmune Encephalomyelitis (EAE)
Intraperitoneal injection
0.1 mg/kg
Daily for 20 days
SB225002 significantly ameliorated EAE in ELT mice.
Nat Commun. 2021 Jan 4;12(1):105
Mice
G422 glioma model
Intraperitoneal injection
10 mg/kg
Daily for 14 days
To inhibit CXCL1 signaling, reduce MDSC accumulation, and slow tumor growth
Acta Pharm Sin B. 2023 Dec;13(12):4733-4747.
B6C3F1 mice
Subcutaneous ovarian cancer model
Intraperitoneal injection
1 mg/kg
Twice a week, until the end of the experiment
SB225002 retarded tumour growth by inhibiting CXCR2 signaling and increased the activity of CD8+ T cells.
Br J Cancer. 2020 Oct;123(9):1404-1416
Mice
Type-B EAE model
Intraperitoneal injection
0.1 mg/kg
Once daily for 20 days
SB225002 significantly ameliorated Type-B EAE but had no effect on Type-A EAE.
Nat Neurosci. 2016 Dec;19(12):1599-1609
NOG mice
Mammary fat pad tumor model
Intraperitoneal injection
0.5 mg/kg
Daily, throughout the treatment cycle
To evaluate the effect of SB225002 on tumor growth and the proportion of CD44+CD24low/? TICs, results showed that SB225002 significantly inhibited MTD-CAFs-induced tumor growth and the increase in CD44+CD24low/? TICs.
J Exp Med. 2016 Dec 12;213(13):2967-2988.
Mice
RMA tumor model
Intraperitoneal injection
0.8 mM
Every 2 days until the end of the experiment
To study the effect of SB225002 on RMA tumor growth
J Exp Med. 2013 Aug 26;210(9):1711-28.
Mice
B16-F10 melanoma model
Intraperitoneal injection
2 mg/kg
Daily until the end of the experiment
Inhibited HFHCD-induced tumor growth acceleration by blocking myeloid cell migration into the tumor
Displacement of [125I]IL8 from human recombinant CXCR2 expressed in CHO cells, IC50=22 nM
17236763
HEK293 cells
Function assay
Antagonist activity at human CXCR2 expressed in HEK293 cells assessed as inhibition of CXCL8-induced intracellular Ca2+ release by fluorescence based calcium flux assay, IC50=40 nM
25254640
human PMNs
Function assay
Antagonist activity at CXCR2 in human PMNs assessed as inhibition of CXCL1-induced intracellular Ca2+ release by fluorescence based calcium flux assay, IC50=30 nM
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