PQ 401 is an IGF-1R inhibitor. PQ401 inhibits breast cancer cell growth in culture and in vivo. PQ401 inhibited autophosphorylation of the IGF-IR in cultured human MCF-7 cells with an IC50 of 12 micromol/L and autophosphorylation of the isolated kinase domain of the IGF-IR with an IC50 <1 micromol/L. In addition, PQ401 inhibited the growth of cultured breast cancer cells in serum at 10 micromol/L. PQ401 was even more effective at inhibiting IGF-I-stimulated growth of MCF-7 cells (IC50, 6 micromol/L). Treatment of MCF-7 cells with PQ401 was associated with a decrease in IGF-I-mediated signaling through the Akt antiapoptotic pathway. Twenty-four hours of treatment with 15 micromol/L PQ401 induced caspase-mediated apoptosis. In vivo, treatment with PQ401 (i.p. injection thrice a week) reduced the growth rate of MCNeuA cells implanted into mice. The IGF-1R tyrosine kinase inhibitor PQ401 inhibited growth of SCC-25 and Cal27 cells alone and also acted synergistically with gefitinib.
|Cell lines||MCF-7 cells|
|Preparation method||Effects of Diaryl Urea on IGF-I Stimulated Proliferation of Breast Cancer Cells MCF-7 cells were harvested by washing thrice with PBS and dissociating with 1 mL 0.05% trypsin. Cells were resuspended in 5 mL defined medium (1:1 Ham's F12/DMEM 4.5 g/L glucose; 1 mg/mL bovine serum albumin; 10 μg/mL transferrin; 15 mmol/L HEPES pH 7.2; 2 mmol/L L-glutamine; 100 units/mL penicillin G; 100 μg/mL streptomycin SO4; 2.5 μg/mL fungizone) containing 200 μg soybean trypsin inhibitor. Cells were plated in 96-well collagen-coated plates (Sigma) at a density of 5,000 per well in 100-μL medium. Twenty hours later, defined medium with or without IGF-I (10 nmol/L) was added. Four hours later, PQ401 diluted in defined medium was added. Plates were harvested on day 3, as described above, for determination of cell number by CyQuant assay.|
|Concentrations||0, 2.5, 5, 7.5, 15, 30µM|
|Incubation time||3 days|
|Animal models||MCNeuA tumor cells bearing mice model|
|Formulation||8% polysorbate 80/ethanol/PBS|
|Dosages||50 or 100 mg/kg|
|Administration||i.p. thrice a week|
|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.
Activation of the insulin-like growth factor-1 receptor induces resistance to epidermal growth factor receptor antagonism in head and neck squamous carcinoma cells.
Jameson MJ, et al. Mol Cancer Ther. 2011 Nov;10(11):2124-34. PMID: 21878657.
Autocrine loop for IGF-I receptor signaling in SLUG-mediated epithelial-mesenchymal transition.
Sivakumar R, et al. Int J Oncol. 2009 Feb;34(2):329-38. PMID: 19148466.
Diarylureas are small-molecule inhibitors of insulin-like growth factor I receptor signaling and breast cancer cell growth.
Gable KL, et al. Mol Cancer Ther. 2006 Apr;5(4):1079-86. PMID: 16648580.
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