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ABSTRACT: BACKGROUND & PURPOSE: Previously, we have shown that sorafenib sensitizes hepatocellular carcinoma (HCC) to TRAIL-induced apoptosis. Here, we report that sorafenib and SC-49 sensitize HCC cells to CS-1008, a novel anti-human death receptor 5 antibody. EXPERIMENTAL APPROACH: HCC cell lines (PLC5, Huh-7, and Hep3B) were treated with CS-1008 and/or sorafenib and analyzed in terms of apoptosis, signal transductions. KEY RESULTS: SC-49 is a sorafenib derivative which is devoid of kinase inhibition activity. Our data indicated that sorafenib as well as SC-49 down-regulated the phosphorylation of signal transducers and activators of transcription 3 (p-STAT3) at Tyr 705 and subsequently reduced the protein levels of STAT3-regulated proteins, Mcl-1, survivin and cylcin D1, in CS-1008-treated HCC cells. Knockdown of STAT3 by RNA-interference overcame apoptotic resistance to CS-1008 in HCC cells, and ectopic expression of STAT3 in HCC cells abolished the sensitizing effect of sorafenib or SC-49 on CS-1008-induced apoptosis, indicating that inhibition of STAT3 mediates the effects of the combination. Importantly, inhibition of SHP-1 by adding a specific SHP-1 inhibitor reduced the effects of SC-49 and CS-1008 on p-STAT3 and apoptosis, whereas co-treatment of CS-1008 and SC-49 increased the activity of SHP-1, suggesting that SHP-1 mediated the combinational effect of CS-1008 and SC-49 in HCC. Moreover, the combination of CS-1008 and SC-49 inhibited HCC xenograft tumor growth in vivo. CONCLUSIONS & IMPLICATIONS: Sorafenib and its derivative SC-49 sensitize HCC to CS-1008 through SHP-1-dependent STAT3 inactivation.
British Journal of Pharmacology 09/2012; · 4.41 Impact Factor
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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.
Journal of Orthopaedic Research 08/2012; · 2.81 Impact Factor
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ABSTRACT: Triple negative breast cancer (TNBC) is very aggressive and currently has no specific therapeutic targets, such as hormone receptors or human epidermal growth factor receptor type 2 (HER2); therefore, prognosis is poor. Bortezomib, a proteasome inhibitor, may exert efficacy in TNBC through its multiple cellular effects. Here, we tested the efficacy of bortezomib and examined the drug mechanism in breast cancer cells.
Five breast cancer cell lines: TNBC HCC-1937, MDA-MB-231, and MDA-MB-468; HER2-overexpressing MDA-MB-453; and estrogen receptor positive MCF-7 were used for in vitro studies. Apoptosis was examined by both flow cytometry and Western Blot. Signal transduction pathways in cells were assessed by Western Blot. Gene silencing was done by small interfering RNA (siRNA). In vivo efficacy of bortezomib was tested in nude mice with breast cancer xenografts. Immunohistochemical study was performed on tumor tissues from patients with TNBC.
Bortezomib induced significant apoptosis, which was independent of its proteasome inhibition, in the three TNBC cell lines, but not in MDA-MB-453 or MCF-7 cells. Furthermore, cancerous inhibitor of protein phosphatase 2A (CIP2A), a cellular inhibitor of protein phosphatase 2A (PP2A), mediated the apoptotic effect of bortezomib. We showed that bortezomib inhibited CIP2A in association with p-Akt downregulation in a dose- and time-dependent manner in all sensitive TNBC cells, whereas no alterations in CIP2A expression and p-Akt were noted in bortezomib-resistant cells. Overexpression of CIP2A upregulated p-Akt and protected MDA-MB-231 and MDA-MB-468 cells from bortezomib-induced apoptosis, whereas silencing CIP2A by siRNA overcame the resistance to bortezomib-induced apoptosis in MCF-7 cells. In addition, bortezomib downregulated CIP2A mRNA but did not affect the degradation of CIP2A protein. Furthermore, bortezomib exerted in vivo antitumor activity in HCC-1937 xenografted tumors, but not in MCF-7 tumors. Bortezomib downregulated CIP2A expression in the HCC-1937 tumors but not in the MCF-7 tumors. Importantly, CIP2A expression is readily detectable in tumor samples from TNBC patients.
CIP2A is a major determinant mediating bortezomib-induced apoptosis in TNBC cells. CIP2A may thus be a potential therapeutic target in TNBC.
Breast cancer research: BCR 04/2012; 14(2):R68. · 5.24 Impact Factor
