https://scholars.lib.ntu.edu.tw/handle/123456789/375905
標題: | Novel sorafenib analogues induce apoptosis through SHP-1 dependent STAT3 inactivation in human breast cancer cells | 作者: | Kuen-Feng Chen | 公開日期: | 2013 | 卷: | 15 | 期: | 4 | 來源出版物: | Breast Cancer Research | 摘要: | Introduction: Signal transducers and activators of transcription 3 (STAT3) signaling is constitutively activated in various cancers including breast cancer and has emerged as a novel potential anti-cancer target. STAT3 has been demonstrated to be a target of sorafenib, and a protein tyrosine phosphatase Src homology 2-domain containing tyrosine phosphatase 1 (SHP-1) has been demonstrated to downregulate p-STAT3 via its phosphatase activity. Here, we tested the efficacy of two sorafenib analogues, SC-1 and SC-43, in breast cancer cells and examined the drug mechanism.Methods: Breast cancer cell lines were used for in vitro studies. Cell viability was examined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was examined by flow cytometry and western blot. Signal transduction pathways in cells were assessed by western blot. In vivo efficacy of sorafenib, SC-1 and SC-43 was tested in xenografted nude mice.Results: SC-1 and SC-43 induced more potent apoptosis than sorafenib, in association with downregulation of p-STAT3 and its downstream proteins cyclin D1 and survivin in a dose-dependent manner in breast cancer cell lines (HCC-1937, MDA-MB-468, MDA-MB-231, MDA-MB-453, SK-BR3, MCF-7). Overexpression of STAT3 in MDA-MB-468 cells protected the cells from apoptosis induced by sorafenib, SC-1 and SC-43. Moreover, SC-1 and SC-43 upregulated SHP-1 activity to a greater extent than sorafenib as measured by in vitro phosphatase assays. Knockdown of SHP-1 by siRNA reduced apoptosis induced by SC-1 and SC-43. Importantly, SC-1 and SC-43 showed more efficacious antitumor activity and p-STAT3 downregulation than sorafenib in MDA-MB-468 xenograft tumors.Conclusions: Novel sorafenib analogues SC-1 and SC-43 induce apoptosis through SHP-1 dependent STAT3 inactivation and demonstrate greater potency than sorafenib in human breast cancer cells. ? 2013 Liu et al.; licensee BioMed Central Ltd. |
URI: | http://www.scopus.com/inward/record.url?eid=2-s2.0-84881269149&partnerID=MN8TOARS http://scholars.lib.ntu.edu.tw/handle/123456789/375905 |
DOI: | 10.1186/bcr3457 | SDG/關鍵字: | antineoplastic agent; cyclin D1; protein tyrosine phosphatase SHP 1; Raf protein; sc 1; sc 43; small interfering RNA; sorafenib; STAT3 protein; survivin; unclassified drug; antineoplastic agent; carbanilamide derivative; nicotinamide; protein kinase inhibitor; protein tyrosine phosphatase SHP 1; Raf protein; sorafenib; STAT3 protein; animal experiment; animal model; antineoplastic activity; antiproliferative activity; apoptosis; article; breast cancer; breast carcinoma; cell proliferation; cell viability; cells; competitive inhibition; controlled study; down regulation; drug efficacy; flow cytometry; human; human cell; immunohistochemistry; immunoreactivity; in vitro study; in vivo study; mouse; nonhuman; protein expression; protein phosphorylation; signal transduction; stable expression; upregulation; Western blotting; analogs and derivatives; breast tumor; cell survival; drug effects; female; gene expression; genetics; metabolism; phosphorylation; tumor cell line; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Down-Regulation; Female; Gene Expression; Humans; Immunohistochemistry; Niacinamide; Phenylurea Compounds; Phosphorylation; Protein Kinase Inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Proto-Oncogene Proteins c-raf; STAT3 Transcription Factor |
顯示於: | 醫學系 |
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