AS101 is an immunomodulator which can inhibit IL-10 synthesis. The IL-10 production could be inhibited by AS101 at concentration ranging in 0.1-2.5μg/ml in a dose-dependent manner in all cell lines including B16 melanoma, stomach adenocarcinoma and GBM cells, and thus reducing clonogenicity of tumor cells. Treatment with AS101 at 1 μg/ml inhibited constitutive stat3 phosphorylation, the best characterized component of IL-10 signaling pathway, in B16 melanoma cells. Through this inhibition of constitutive Stat3 activation by virtue of the autocrine/paracrine IL-10 loop through AS101 in B16 cells, AS101 could sensitize B16 melanoma cells to chemotherapy including paclitaxel, doxorubicin and 5-fluorouracil by ~20%. And this effect could also be observed in GBM tumor model to paclitaxel via inhibition of IL-10 by administration of AS101 at dose of 0.5mg/kg, i.p.[1]. Treatment with AS101 at concentration ranging in 0.5-2.5μg/ml could increase SIRT1 levels in HEK293, HL‐60 and Rin-5f cells post 48h treatment. And robust increase of SIRT1 protein level could be observed in a time- and dose-dependent manner in livers of rats daily, i.p., dosed with 0.25-1mg/kg AS101 for 5-28 days, through a possible mechanism of serum IGF-1 reduction. Treatment with AS101 before manifestation of hyperglycemia could result in increased insulin sensitivity, and decreased blood glucose levels, and prevented symptoms of diabetes including defective glucose clearance, fatty liver, and abnormal distribution of insulin-producing beta cells in the pancreas. Also, treatment after disease emergence resulted in partial restoration of normal glucose homeostasis[2].
作用机制
AS101 may work as an ICE (interleukin-1βconverting enzyme, caspase-1) activity inhibitor.[3]
AS101 promotes Treg differentiation independently of TGF-β
J Autoimmun. 2019 Jun;100:52-61.
R161H LN cells
0.1, 0.3, 1 μg/ml
72 h
AS101 inhibits Th1 and Th17 polarization, reducing IFN-γ and IL-17A expressing cells
J Autoimmun. 2019 Jun;100:52-61.
MLN cells
0.1, 0.5, 1 µg/ml
2 h
AS101 significantly reduced the adhesion of MLN cells to MAdCAM-1
J Biol Chem. 2014 Jun 13;289(24):17215-27.
glomerular macrophages
1 µg/ml
24 h
AS101 significantly inhibited IL-1β secretion and caspase-1 activity in macrophages, indicating that AS101 inhibits caspase-1 activation by suppressing VLA-4 activity.
Front Immunol. 2017 Mar 7;8:240.
Ossirene 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6 mice
B16/F10 melanoma model
Intraperitoneal injection
1 mg/kg
Every other day, until tumor volume reached 2000 mm³
AS101 significantly reduced tumor volume, decreased PD-L1 expression on tumor cells, and increased CD8+ T-cell infiltration into the tumor
Int J Biol Sci. 2024 Aug 12;20(11):4407-4423.
Mice
Experimental autoimmune uveitis (EAU)
Intraperitoneal injection
27 μg/mouse
Daily for 14 consecutive days
AS101 increases Treg cells, reduces Th1 and Th17 effector cells, and attenuates EAU
J Autoimmun. 2019 Jun;100:52-61.
C57BL/6 mice
DSS-induced colitis model
Intraperitoneal or oral
10 µg/mouse (intraperitoneal) or 100 µg/mouse (oral)
Daily administration for 7 days
AS101 significantly alleviated clinical symptoms of DSS-induced colitis, reduced inflammatory cell infiltration, and protected colonic epithelial barrier function
J Biol Chem. 2014 Jun 13;289(24):17215-27.
Rats
Crescentic glomerulonephritis model
Intraperitoneal injection
100 µg/rat
Daily injections for 21 days
AS101 significantly improved renal function, reduced crescent formation, and inhibited inflammatory mediators and macrophage infiltration in the crescentic glomerulonephritis model.
搜索
