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学科主题: 基础医学
题名:
YC-1 enhances the anti-tumor activity of sorafenib through inhibition of signal transducer and activator of transcription 3 (STAT3) in hepatocellular carcinoma
作者: Kong, Jian1; Kong, Fandong1; Gao, Jun1; Zhang, Qiangbo6; Dong, Shuying1; Gu, Fang7; Ke, Shan1; Pan, Bing2,3,4; Shen, Qiang2,3,4; Sun, Huichuan5; Zheng, Lemin2,3,4; Sun, Wenbing1
关键词: YC-1 ; Sorafenib ; Hepatocellular carcinoma ; STAT3
刊名: MOLECULAR CANCER
发表日期: 2014-01-13
DOI: 10.1186/1476-4598-13-7
卷: 13
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Biochemistry & Molecular Biology ; Oncology
研究领域[WOS]: Biochemistry & Molecular Biology ; Oncology
关键词[WOS]: INDUCIBLE FACTOR-1 ALPHA ; CANCER CELL-LINE ; IN-VIVO ; APOPTOSIS ; PATHWAY ; RESISTANCE ; RECEPTOR ; GROWTH ; METASTASIS ; ANTICANCER
英文摘要:

Background: Traditional systemic chemotherapy does not provide survival benefits in patients with hepatocellular carcinoma (HCC). Molecular targeted therapy shows promise for HCC treatment, however, the duration of effectiveness for targeted therapies is finite and combination therapies offer the potential for improved effectiveness.

Methods: Sorafenib, a multikinase inhibitor, and YC-1, a soluble guanylyl cyclase (sGC) activator, were tested in HCC by proliferation assay, cell cycle analysis and western blot in vitro and orthotopic and ectopic HCC models in vivo.

Results: In vitro, combination of sorafenib and YC-1 synergistically inhibited proliferation and colony formation of HepG2, BEL-7402 and HCCLM3 cells. The combination also induced S cell cycle arrest and apoptosis, as observed by activated PARP and caspase 8. Sorafenib and YC-1 respectively suppressed the expression of phosphorylated STAT3 (p-STAT3) (Y705) in a dose-and time-dependent manner. Combination of sorafenib and YC-1 significantly inhibited the expression of p-STAT3 (Y705) (S727), p-ERK1/2, cyclin D1 and survivin and SHP-1 activity compared with sorafenib or YC-1 used alone in all tested HCC cell lines. In vivo, sorafenib-YC-1 combination significantly suppressed the growth of HepG2 tumor xenografts with decreased cell proliferation and increased apoptosis observed by PCNA and PARP. Similar results were also confirmed in a HCCLM3 orthotopic model. There was a reduction in CD31-positive blood vessels and reduced VEGF expression, which suggested a combinational effect of sorafenib and YC-1 on angiogenesis. The reduced expression of p-STAT3, cyclin D1 and survivin was also observed with the combination of sorafenib and YC-1.

Conclusions: Our data show that sorafenib-YC-1 combination is a novel potent therapeutic agent that can target the STAT3 signaling pathway to inhibit HCC tumor growth.

语种: 英语
所属项目编号: 320675007131 ; 32067501207 ; 2010CB912504 ; 2011CB503900 ; 81170101 ; 81370235 ; 30821001 ; 7122106
项目资助者: Dr. Jieping Wu Medical Foundation ; Program for Medical Key Discipline of Shijingshan District, Beijing ; "973" National ST Major Project ; National Natural Science Foundation of China ; Natural Science Foundation of Beijing, China
WOS记录号: WOS:000331564200001
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/56545
Appears in Collections:基础医学院_心血管所_期刊论文

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作者单位: 1.Capital Med Univ, Beijing Chaoyang Hosp, Dept Hepatobiliary Surg, Beijing 100043, Peoples R China
2.Peking Univ, Hlth Sci Ctr, Key Lab Mol Cardiovasc Sci, Inst Cardiovasc Sci,Educ Minist,Sch Basic Med Sci, Beijing 100191, Peoples R China
3.Peking Univ, Hlth Sci Ctr, Key Lab Mol Cardiovasc Sci, Inst Syst Biomed,Educ Minist,Sch Basic Med Sci, Beijing 100191, Peoples R China
4.Minist Hlth, Key Lab Cardiovasc Mol Biol & Regulatory Peptides, Beijing 100191, Peoples R China
5.Fudan Univ, Zhongshan Hosp, Liver Canc Inst, Shanghai 200032, Peoples R China
6.Shandong Univ, Qilu Hosp, Dept Gen Surg, Jinan 250012, Peoples R China
7.Chinese Peoples Liberat Army Gen Hosp, Dept Obstet & Gynecol, Beijing 100853, Peoples R China

Recommended Citation:
Kong, Jian,Kong, Fandong,Gao, Jun,et al. YC-1 enhances the anti-tumor activity of sorafenib through inhibition of signal transducer and activator of transcription 3 (STAT3) in hepatocellular carcinoma[J]. MOLECULAR CANCER,2014,13.
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