Src kinases are regulators of the expression of connective tissue growth factor (CTGF/CCN2), which plays a role in fibrotic injuries[3]. SU6656 is a small-molecule indolinone that selectively inhibits Src family kinase and induces death of cancer cells[4]. Src family protein tyrosine kinases (SFKs) inhibitor SU6656 caused proliferation abrogation as a result of the formation of cells with single multilobed nuclei and several mitotic spindle poles, features similar to polyploid megakaryocytes[5]. Four-month-old female C57Bl/6J mice received intraperitoneal injections of either 25 mg/kg SU6656 or its vehicle every other day for 12 weeks. SU6656-treated mice exhibited increased bone mineral density, cortical thickness, cancellous bone volume and trabecular thickness. SU6656 inhibited bone resorption in mice as shown by reduced osteoclast number, and diminished expressions of Oscar, Trap5b and CtsK. SU6656 did not affect Rankl or Opg expressions[6]. SU6656 reduced TNF-α-mediated paracellular permeability changes, restored occludin, p120, and E-cadherin and lowered autocrine TNF-α release. SU6656 improved the barrier properties of severe asthmatic air-liquid interface cultures[7]. Ischemic postconditioning induced neuroprotective effects were significantly attenuated by pre-treatment of selective Src Kinase inhibitors SU-6656 (4 mg/kg i.p.) and PP1 (0.2 mg/kg i.p.)[8].
SU6656 细胞实验
Cell Line
Concentration
Treated Time
Description
References
A431-III cells
10 µM
24 hours
Reduced invasive ability
Antioxidants (Basel). 2019 Nov 15;8(11):557
SYF cells
100 µM
1 hour
SU6656 still activates AMPK and increases Thr172 phosphorylation in SYF cells lacking Src family kinases
Cell Chem Biol. 2017 Jul 20;24(7):813-824. e4
HeLa cells
100 µM
1 hour
SU6656 activates AMPK in HeLa cells but does not activate any AMPK-related kinases (ARKs)
Cell Chem Biol. 2017 Jul 20;24(7):813-824. e4
HEK293 cells
1-100 µM
1 hour
SU6656 activates AMPK and increases Thr172 phosphorylation, along with increased phosphorylation of downstream target ACC but not Raptor
Cell Chem Biol. 2017 Jul 20;24(7):813-824. e4
Bt-549 cells
10 µM
1 hour
Inhibition of c-Src activity significantly enhanced microtentacle formation
Oncogene. 2010 Dec 2;29(48):6402-8
MDA-MB-231 cells
10 µM
1 hour
Inhibition of c-Src activity significantly enhanced microtentacle formation while suppressing invadopodia
Oncogene. 2010 Dec 2;29(48):6402-8
Pulmonary artery smooth muscle cells (PASMCs)
3 µM and 30 µM
10 min
Inhibited hypoxic pulmonary vasoconstriction, particularly the sustained phase
To investigate the effect of SU6656 on LKB1 subcellular localization, results showed that SU6656 treatment caused redistribution of LKB1 from the nucleus to the cytoplasm.
Cell Metab. 2010 Feb 3;11(2):113-24
E13 rat commissural neurons
0.5, 1, 2 µM
2 hours
SU6656 inhibits Netrin-1-induced tyrosine phosphorylation of DCC
J Cell Biol. 2004 Nov 22;167(4):687-98.
Rat oligodendrocytes
20 µM
24 hours
Inhibited Lyn kinase activity and restored apoptotic signaling in oligodendrocytes
Glia. 2010 Nov 15;58(15):1782-93
A431-III cells
1, 5, 10 µM
24 hours
Reduced protein levels of S100A7, p-Src, and p-Stat3
Antioxidants (Basel). 2019 Nov 15;8(11):557
Lung cancer cells
5 µM
24, 48, 72 hours
Inhibition of Src activity increases FABP4 expression and reduces lipid droplet accumulation
EBioMedicine. 2019 Mar;41:134-145
CD34+ HPCs
2.5 µM
4 days
Increased megakaryocyte ploidy and size, reduced terminal injury and apoptosis
Blood Adv. 2018 Mar 27;2(6):597-606
Endothelial progenitor cells (EPCs)
2 µM
4 hours
Inhibited SDF-1-induced migration of EPCs
J Mol Cell Cardiol. 2015 Apr;81:49-53
Bone marrow mononuclear cells (BM MNCs)
2 µM
4 hours
Inhibited SDF-1-induced migration of BM MNCs
J Mol Cell Cardiol. 2015 Apr;81:49-53
Primary hepatocytes from male Wistar rats
15 µM
4 hours
To investigate the effect of SU6656 on fasting-induced triglyceride (TG) loss. Results showed that SU6656 significantly blocked fasting-induced TG loss in control hepatocytes but had minimal effect on hepatocytes from ethanol-fed rats, likely due to pre-existing impaired lipophagy.
Hepatol Commun. 2017 Aug;1(6):501-512
Human macrophages
20 µM
5 hours
Inhibited macrophage macropinocytosis, reducing LDL uptake and cholesterol accumulation by approximately 40%
Inhibition of Src kinases reduced SMC death from H2O2 exposure in PCAs from young males but had no significant effect in old males.
Aging Cell. 2024 May;23(5):e14110.
Human pulmonary artery endothelial cells (HPAECs)
3-6 µM
6 hours
SU6656 partially attenuated KOdiA-PC–induced NF-κB phosphorylation and ICAM-1 expression, but more complete inhibition was achieved in cells coincubated with L37pA.
Am J Respir Cell Mol Biol. 2024 Jan;70(1):11-25
SU6656 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Sprague-Dawley rats
Pressure-natriuresis model
Intravenous infusion
10 µmol/kg/min
60 minutes
SU6656 inhibited cGMP-induced natriuresis, indicating that Src-family kinase plays an important role in the signaling pathway of cGMP-induced natriuresis.
Hypertension. 2011 Jul;58(1):107-13
Balb/c nude mice
Lung cancer xenograft model
Intraperitoneal injection
20 mg/kg
Every other day for 23 days
Inhibition of Src activity reduces tumor growth and lipid droplet accumulation
EBioMedicine. 2019 Mar;41:134-145
C57BL/6J mice
Silicosis model
Intraperitoneal injection
3 mg/kg/day
Once daily from day 8 to day 28
SU6656 attenuated the activation of the PI3K/AKT pathway by inhibiting the phosphorylation of c-Src, thereby suppressing fibrosis in the silicosis model.
Subcutaneous xenograft tumor model of A431/H9 or CA46 cells
Intraperitoneal injection
300 μg
Three doses injected every other day
SU6656 combined with SS1P or HA22 showed synergistic antitumor effects in mouse xenograft tumor models
Mol Cancer Ther. 2014 Jan;13(1):82-9
C57BLK6/J mice
Wild type mice
Intraperitoneal injection
4 mg/kg
Single injection, monitored for 12 hours
To investigate the effect of SU6656 on energy expenditure and fatty acid oxidation, results showed that SU6656 treatment increased energy expenditure and fatty acid oxidation, leading to reduced fat mass.
Cell Metab. 2010 Feb 3;11(2):113-24
Mice
Myocardial infarction model
Intraperitoneal injection
6 mg/kg
Single dose
Reduced recruitment of BM PCs to ischemic myocardium
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