Please use this identifier to cite or link to this item:
https://doi.org/10.3892/ijo.2012.1494
DC Field | Value | |
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dc.title | Combination of the ERK inhibitor AZD6244 and low-dose sorafenib in a xenograft model of human renal cell carcinoma | |
dc.contributor.author | Yuen, J.S.P | |
dc.contributor.author | Sim, M.Y | |
dc.contributor.author | Sim, H.G | |
dc.contributor.author | Chong, T.W | |
dc.contributor.author | Lau, W.K.O | |
dc.contributor.author | Cheng, C.W.S | |
dc.contributor.author | Ong, R.W | |
dc.contributor.author | Huynh, H | |
dc.date.accessioned | 2020-10-27T04:53:08Z | |
dc.date.available | 2020-10-27T04:53:08Z | |
dc.date.issued | 2012 | |
dc.identifier.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 | |
dc.identifier.issn | 1019-6439 | |
dc.identifier.uri | https://scholarbank.nus.edu.sg/handle/10635/180827 | |
dc.description.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. | |
dc.rights | Attribution 4.0 International | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.source | Unpaywall 20201031 | |
dc.subject | BIM protein | |
dc.subject | cyclin B1 | |
dc.subject | cyclin dependent kinase 2 | |
dc.subject | mitogen activated protein kinase | |
dc.subject | p70s6k protein | |
dc.subject | p90rsk protein | |
dc.subject | platelet derived growth factor beta receptor | |
dc.subject | protein | |
dc.subject | protein BAD | |
dc.subject | protein p27 | |
dc.subject | selumetinib | |
dc.subject | sorafenib | |
dc.subject | survivin | |
dc.subject | unclassified drug | |
dc.subject | vasculotropin receptor 2 | |
dc.subject | angiogenesis | |
dc.subject | animal experiment | |
dc.subject | animal model | |
dc.subject | animal tissue | |
dc.subject | antiangiogenic activity | |
dc.subject | antineoplastic activity | |
dc.subject | apoptosis | |
dc.subject | article | |
dc.subject | cancer combination chemotherapy | |
dc.subject | cancer inhibition | |
dc.subject | cell cycle arrest | |
dc.subject | cell cycle G0 phase | |
dc.subject | cell cycle G1 phase | |
dc.subject | cell cycle G2 phase | |
dc.subject | cell cycle S phase | |
dc.subject | cell migration | |
dc.subject | cell proliferation | |
dc.subject | concentration response | |
dc.subject | controlled study | |
dc.subject | down regulation | |
dc.subject | drug dose reduction | |
dc.subject | drug efficacy | |
dc.subject | human | |
dc.subject | human cell | |
dc.subject | immunoblotting | |
dc.subject | immunohistochemistry | |
dc.subject | kidney carcinoma | |
dc.subject | low drug dose | |
dc.subject | male | |
dc.subject | microvasculature | |
dc.subject | mouse | |
dc.subject | nonhuman | |
dc.subject | priority journal | |
dc.subject | protein phosphorylation | |
dc.subject | retinoblastoma | |
dc.subject | tumor volume | |
dc.subject | tumor xenograft | |
dc.subject | upregulation | |
dc.subject | Western blotting | |
dc.subject | Angiogenesis Inhibitors | |
dc.subject | Animals | |
dc.subject | Antineoplastic Combined Chemotherapy Protocols | |
dc.subject | Benzenesulfonates | |
dc.subject | Benzimidazoles | |
dc.subject | Carcinoma, Renal Cell | |
dc.subject | Cell Proliferation | |
dc.subject | Humans | |
dc.subject | Kidney Neoplasms | |
dc.subject | Mice | |
dc.subject | Mitogen-Activated Protein Kinase 3 | |
dc.subject | Phosphorylation | |
dc.subject | Poly(ADP-ribose) Polymerases | |
dc.subject | Protein Processing, Post-Translational | |
dc.subject | Pyridines | |
dc.subject | Receptor, Platelet-Derived Growth Factor beta | |
dc.subject | Tumor Burden | |
dc.subject | Tumor Cells, Cultured | |
dc.subject | Vascular Endothelial Growth Factor Receptor-2 | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.type | Article | |
dc.contributor.department | MEDICINE | |
dc.contributor.department | SURGERY | |
dc.contributor.department | DUKE-NUS MEDICAL SCHOOL | |
dc.description.doi | 10.3892/ijo.2012.1494 | |
dc.description.sourcetitle | International Journal of Oncology | |
dc.description.volume | 41 | |
dc.description.issue | 2 | |
dc.description.page | 712-720 | |
dc.published.state | Published | |
Appears in Collections: | Staff Publications Elements |
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