Abstract
Osteosarcoma (OS) is the leading primary malignant bone tumor in children and young adults. It is response for a high mortality rate. Nowadays, few researches have been performed on sorafenib against OS and no tools are available to guide the use of sorafenib in the OS treatment. In this study, we aim to investigate the effect of sorafenib on OS cell MG63 and figure the potential effective molecular pathway of its function. In the present study, we performed assays of cell proliferation, RT-PCR, and western blot to investigate the effect of sorafenib on OS MG63 cells and to elucidate the molecular actions of sorafenib against RTKs VEGFR2 and RET, as well as MEK/ERK signaling pathway. The present study confirmed that sorafenib could inhibit the proliferation of OS MG63 cells and caused a series of biomolecule effects, including the change of VEGFR2 and ERK gene expression, and the phosphorylation alteration of VEGFR2, RET, and MEK1 proteins. VEGFR2, RET, and MEK/ERK signaling pathway are involved in the pharmacological mechanism of sorafenib. They are potential candidate targets for OS treatment.
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Ferrari, S., Smeland, S., Mercuri, M., Bertoni, F., Longhi, A., Ruggieri, P., et al. (2005). Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: A joint study by the Italian and Scandinavian Sarcoma Groups [Clinical Trial Comparative Study Multicenter Study]. Journal of Clinical Oncology, 23(34), 8845–8852.
Ozaki, T., Flege, S., Kevric, M., Lindner, N., Maas, R., Delling, G., et al. (2003). Osteosarcoma of the pelvis: experience of the Cooperative Osteosarcoma Study Group [Multicenter Study Research Support, Non-U.S. Gov’t]. Journal of Clinical Oncology, 21(2), 334–341.
Smithey, B. E., Pappo, A. S., & Hill, D. A. (2002). C-kit expression in pediatric solid tumors: a comparative immunohistochemical study [Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, P.H.S.]. The American Journal of Surgical Pathology, 26(4), 486–492.
McGary, E. C., Weber, K., Mills, L., Doucet, M., Lewis, V., Lev, D. C., et al. (2002). Inhibition of platelet-derived growth factor-mediated proliferation of osteosarcoma cells by the novel tyrosine kinase inhibitor STI571 [Research Support, U.S. Gov’t, P.H.S.]. Clinical Cancer Research, 8(11), 3584–3591.
Kaya, M., Wada, T., Akatsuka, T., Kawaguchi, S., Nagoya, S., Shindoh, M., et al. (2000). Vascular endothelial growth factor expression in untreated osteosarcoma is predictive of pulmonary metastasis and poor prognosis. Clinical Cancer Research, 6(2), 572–577.
Lyons, J. F., Wilhelm, S., Hibner, B., & Bollag, G. (2001). Discovery of a novel Raf kinase inhibitor [Review]. Endocrine-Related Cancer, 8(3), 219–225.
Sridhar, S. S., Hedley, D., & Siu, L. L. (2005). Raf kinase as a target for anticancer therapeutics. Molecular Cancer Therapeutics, 4(4), 677–685.
Wilhelm, S. M., Carter, C., Tang, L., Wilkie, D., McNabola, A., Rong, H., et al. (2004). BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Research, 64(19), 7099–7109.
Mitsudomi, T. (2010). Advances in target therapy for lung cancer. Japanese Journal of Clinical Oncology, 40(2), 101–106.
Merseburger, A. S., Simon, A., Waalkes, S., & Kuczyk, M. A. (2009). Sorafenib reveals efficacy in sequential treatment of metastatic renal cell cancer [Review]. Expert Review of Anticancer Therapy, 9(10), 1429–1434.
Min, L., He, B., & Hui, L. (2011). Mitogen-activated protein kinases in hepatocellular carcinoma development. Seminars in Cancer Biology, 21(1), 10–20.
Mao, W. F., Shao, M. H., Gao, P. T., Ma, J., Li, H. J., Li, G. L., et al. (2012). The important roles of RET, VEGFR2 and the RAF/MEK/ERK pathway in cancer treatment with sorafenib. Acta Pharmacologica Sinica, 33(10), 1311–1318.
Molina, M. A., Codony-Servat, J., Albanell, J., Rojo, F., Arribas, J., & Baselga, J. (2001). Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells [Research Support, Non-U.S. Gov’t]. Cancer Research, 61(12), 4744–4749.
Heinrich, M. C., Corless, C. L., Demetri, G. D., Blanke, C. D., von Mehren, M., Joensuu, H., et al. (2003). Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor [Clinical Trial Clinical Trial, Phase II Comparative Study Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, Non-P.H.S.]. Journal of Clinical Oncology, 21(23), 4342–4349.
Heinrich, M. C., Maki, R. G., Corless, C. L., Antonescu, C. R., Harlow, A., Griffith, D., et al. (2008). Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor [Clinical Trial, Phase I Clinical Trial, Phase II Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t Research Support, U.S. Gov’t, Non-P.H.S.]. Journal of Clinical Oncology, 26(33), 5352–5359.
Feld, R., Sridhar, S. S., Shepherd, F. A., Mackay, J. A., & Evans, W. K. (2006). Use of the epidermal growth factor receptor inhibitors gefitinib and erlotinib in the treatment of non-small cell lung cancer: A systematic review. Journal of Thoracic Oncology, 1(4), 367–376.
Wolfesberger, B., Tonar, Z., Gerner, W., Skalicky, M., Heiduschka, G., Egerbacher, M., et al. (2010). The tyrosine kinase inhibitor sorafenib decreases cell number and induces apoptosis in a canine osteosarcoma cell line. Research in Veterinary Science, 88(1), 94–100.
Yang, S. Y., Yu, H., Krygier, J. E., Wooley, P. H., & Mott, M. P. (2007). High VEGF with rapid growth and early metastasis in a mouse osteosarcoma model. Sarcoma,. doi:10.1155/2007/95628.
Cuccuru, G., Lanzi, C., Cassinelli, G., Pratesi, G., Tortoreto, M., Petrangolini, G., et al. (2004). Cellular effects and antitumor activity of RET inhibitor RPI-1 on MEN2A-associated medullary thyroid carcinoma [Research Support, Non-U.S. Gov’t]. Journal of the National Cancer Institute, 96(13), 1006–1014.
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Institution of all of the authors has received funding from the National Natural Science Foundation of China (Grant No. 30471760). In addition, we gratefully acknowledge the assistance of Gailing Li in Shanghai Chest Hospital. They gave us some proposals in point.
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Mei, J., Zhu, X., Wang, Z. et al. VEGFR, RET, and RAF/MEK/ERK Pathway Take Part in the Inhibition of Osteosarcoma MG63 Cells with Sorafenib Treatment. Cell Biochem Biophys 69, 151–156 (2014). https://doi.org/10.1007/s12013-013-9781-7
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DOI: https://doi.org/10.1007/s12013-013-9781-7