In vitro: The treatment with PD166866 apparently causes a mitochondrial deficit and an oxidative stress. PD 166866 inhibits human full-length FGFR-1 tyrosine kinase with an IC50 value of 52.4 ± 0.1 nM but has no effect on c-Src, platelet-derived growth factor receptor-β, epidermal growth factor receptor or insulin receptor tyrosine kinases or on mitogen-activated protein kinase, protein kinase C and CDK4 at concentrations as high as 50 μM. PD 166866 is a potent inhibitor of basic fibroblast growth factor (bFGF)-mediated receptor autophosphorylation in NIH 3T3 cells expressing endogenous FGFR-1 and in L6 cells overexpressing the human FGFR-1 tyrosine kinase, confirming a tyrosine kinase-mediated mechanism. PD 166866 does not inhibit platelet-derived growth factor, epidermal growth factor or insulin-stimulated receptor autophosphorylation in vascular smooth muscle, A431 or NIHIR cells, respectively, further supporting its specificity for the FGFR-1. Besides, PD 166866 is found to be a potent inhibitor of microvessel outgrowth (angiogenesis) from cultured artery fragments of human placenta. Phosphorylated 44- and 42-kDa MAPK isoforms are inhibited in L6 cells by PD 166866 with IC50 values of 4.3 and 7.9 nM, respectively. PD166866 induces autophagy through repressing Akt/mTOR signaling pathway.
|Cell lines||HeLa cells|
|Preparation method||HeLa cells are treated with PD166866 for 24 hours, the growth medium is removed, the cells are washed with PBS and fixed for 1 hour at 25°C adding a freshly made paraformaldheyde solution (4% in PBS). Samples are washed again with PBS and the endogenous oxidases were blocked for 2 minutes in the dark. Further washes with PBS followed and blocking the unspecific sites is done for 1 hour at 25℃. PARP is evidenced by immunolocalization utilizing a polyclonal antibody, directed against the N-terminal proteolytic fragment. Immuno-reaction is revealed by a secondary anti-rabbit antibody after incubation for 16 hours at 4°C. After exhaustive washing with PBS the samples are incubated for 30 minutes in solution ABC. Eventually, DAB (3,3'-Diaminobenzidine) is added and the samples are incubated for 10 minutes in the dark. The samples are washed again the plates are sealed and ready for microscopic observation.|
|Incubation time||24 h|
|Animal models||Female nude mice|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||14 mg/mL in DMSO|
FGFR antagonist induces protective autophagy in FGFR1-amplified breast cancer cell.
Chen Y, et al. Biochem Biophys Res Commun. 2016 May 20;474(1):1-7. PMID: 26993162.
Canine and human sarcomas exhibit predominant FGFR1 expression and impaired viability after inhibition of signaling.
Schweiger N, et al. Mol Carcinog. 2015 Sep;54(9):841-52. PMID: 24719266.
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