SC-1, a sorafenib derivative, shows anti-tumor effects in osteogenic sarcoma cells
Journal
Journal of Orthopaedic Research
Journal Volume
31
Journal Issue
2
Pages
335-342
Date Issued
2013
Author(s)
Abstract
Despite significant advances in the treatment of osteosarcoma (OS), overall survival rate of OS patients has remained relatively constant for over two decades and novel approaches are needed to further improve prognosis. Here, we report the anti-tumor effect of SC-1, a novel sorafenib derivative that closely resembles sorafenib structurally but is devoid of kinase inhibitory activity, on OS cells through mediation of signal transducer and activator of transcription 3 (STAT3). SC-1 showed similar effects to sorafenib on growth inhibition and apoptosis, and downregulated phospho-STAT3 (p-STAT3) at tyrosine 705 in all tested OS cell lines (U2OS, HOS, and 143B). Expression of STAT3-driven genes, including cylcin D1 and c-myc, were also repressed by SC-1. Ectopic expression of STAT3 in 143B cells abolished apoptosis in SC-1-treated cells. Inhibition of SHP-1 decreased SC-1-induced apoptosis. SC-1 upregulated the activity of SHP-1 in tested OS cell lines in a dose-dependent manner. Finally, SC-1 reduced 143B tumor growth significantly in vivo, which was associated with downregulation of p-STAT3 and upregulation of SHP-1 activity. These data demonstrate that SC-1 has clinical potential for the treatment of OS patients. ? 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 335-342, 2013 Copyright ? 2012 Orthopaedic Research Society.
SDGs
Other Subjects
antineoplastic agent; cyclin D1; Myc protein; protein tyrosine phosphatase SHP 1; sc 1; sorafenib; STAT3 protein; tyrosine; unclassified drug; animal experiment; animal model; animal tissue; antineoplastic activity; apoptosis; article; cancer cell culture; controlled study; dose response; down regulation; enzyme activity; enzyme induction; enzyme inhibition; gene expression; gene repression; human; human cell; in vivo study; male; mouse; nonhuman; osteosarcoma; osteosarcoma cell; priority journal; tumor growth; Animals; Antineoplastic Agents; Apoptosis; Benzenesulfonates; Bone Neoplasms; Cell Line, Tumor; Humans; Male; Mice; Osteosarcoma; Phenylurea Compounds; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Signal Transduction; STAT3 Transcription Factor
Type
journal article