Please use this identifier to cite or link to this item: https://doi.org/10.3892/ijo.2012.1494
Title: Combination of the ERK inhibitor AZD6244 and low-dose sorafenib in a xenograft model of human renal cell carcinoma
Authors: Yuen, J.S.P 
Sim, M.Y
Sim, H.G 
Chong, T.W 
Lau, W.K.O 
Cheng, C.W.S 
Ong, R.W
Huynh, H 
Keywords: BIM protein
cyclin B1
cyclin dependent kinase 2
mitogen activated protein kinase
p70s6k protein
p90rsk protein
platelet derived growth factor beta receptor
protein
protein BAD
protein p27
selumetinib
sorafenib
survivin
unclassified drug
vasculotropin receptor 2
angiogenesis
animal experiment
animal model
animal tissue
antiangiogenic activity
antineoplastic activity
apoptosis
article
cancer combination chemotherapy
cancer inhibition
cell cycle arrest
cell cycle G0 phase
cell cycle G1 phase
cell cycle G2 phase
cell cycle S phase
cell migration
cell proliferation
concentration response
controlled study
down regulation
drug dose reduction
drug efficacy
human
human cell
immunoblotting
immunohistochemistry
kidney carcinoma
low drug dose
male
microvasculature
mouse
nonhuman
priority journal
protein phosphorylation
retinoblastoma
tumor volume
tumor xenograft
upregulation
Western blotting
Angiogenesis Inhibitors
Animals
Antineoplastic Combined Chemotherapy Protocols
Benzenesulfonates
Benzimidazoles
Carcinoma, Renal Cell
Cell Proliferation
Humans
Kidney Neoplasms
Mice
Mitogen-Activated Protein Kinase 3
Phosphorylation
Poly(ADP-ribose) Polymerases
Protein Processing, Post-Translational
Pyridines
Receptor, Platelet-Derived Growth Factor beta
Tumor Burden
Tumor Cells, Cultured
Vascular Endothelial Growth Factor Receptor-2
Xenograft Model Antitumor Assays
Issue Date: 2012
Citation: Yuen, J.S.P, Sim, M.Y, Sim, H.G, Chong, T.W, Lau, W.K.O, Cheng, C.W.S, Ong, R.W, Huynh, H (2012). Combination of the ERK inhibitor AZD6244 and low-dose sorafenib in a xenograft model of human renal cell carcinoma. International Journal of Oncology 41 (2) : 712-720. ScholarBank@NUS Repository. https://doi.org/10.3892/ijo.2012.1494
Rights: Attribution 4.0 International
Abstract: Sorafenib, a multikinase inhibitor, is currently used as monotherapy for advanced renal cell carcinoma (RCC). However, adverse effects associated with its use have been experienced by some patients. In this study, we examined the antitumor and antiangiogenic activities of low-dose sorafenib in combination with the MEK inhibitor AZD6244 (sorafenib/AZD6244) in a preclinical model of RCC. Primary RCC 08-0910 and RCC 786-0 cells as well as patient-derived RCC models were used to study the antitumor and antiangiogenic activities of sorafenib/AZD6244. Changes of biomarkers relevant to angiogenesis and cell cycle were determined by western immunoblotting. Microvessel density, apoptosis and cell proliferation were analyzed by immunohistochemistry. Treatment of RCC 786-0 cells with sorafenib/AZD6244 resulted in G1 cell cycle arrest and blockade of serum-induced cell migration. Sorafenib/AZD6244 induced apoptosis in primary RCC 08-0910 cells at low concentrations. In vivo addition of AZD6244 to sorafenib significantly augmented the antitumor activity of sorafenib and allowed dose reduction of sorafenib without compromising its antitumor activity. Sorafenib/AZD6244 potently inhibited angiogenesis and phosphorylation of VEGFR-2, PDGFR-? and ERK, p90RSK, p70S6K, cdk-2 and retinoblastoma. Sorafenib/AZD6244 also caused upregulation of p27, Bad and Bim but downregulation of survivin and cyclin B1. These resulted in a reduction in cellular proliferation and the induction of tumor cell apoptosis. Our findings showed that AZD6244 and sorafenib complement each other to inhibit tumor growth. This study provides sound evidence for the clinical investigation of low-dose sorafenib in combination with AZD6244 in patients with advanced RCC.
Source Title: International Journal of Oncology
URI: https://scholarbank.nus.edu.sg/handle/10635/180827
ISSN: 1019-6439
DOI: 10.3892/ijo.2012.1494
Rights: Attribution 4.0 International
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