Distinct antifibrogenic effects of erlotinib,sunitinib and sorafenib on rat pancreatic stellate cell

来源 :World Journal of Gastroenterology | 被引量 : 0次 | 上传用户:jimchenstong
下载到本地 , 更方便阅读
声明 : 本文档内容版权归属内容提供方 , 如果您对本文有版权争议 , 可与客服联系进行内容授权或下架
论文部分内容阅读
AIM:To study if three clinically available small molecule kinase inhibitors(SMI),erlotinib,sunitinib and sorafenib,exert antifibrogenic effects on pancreatic stellate cells(PSC)and analyze the basis of their action.METHODS:Cultured rat PSC were exposed to SMI.Cell proliferation and viability were assessed employing 5-bromo-2’-deoxyuridine incorporation assay and flow cytometry,respectively.2-Deoxy-2-[18F]fluoroglucose(18F-FDG)uptake was measured to study metabolic activity.Exhibition of the myofibroblastic PSC phenotype was monitored by immunofluorescence analysis ofα-smooth muscle actin(α-SMA)expression.Levels of mRNA were determined by real-time PCR,while protein expression and phosphorylation were analyzed by immunoblotting.Transforming growth factor-β1 (TGF-β1)levels in culture supernatants were quantified by ELISA.RESULTS:All three SMI inhibited cell proliferation and18F-FDG uptake in a dose-dependent manner and without significant cytotoxic effects.Furthermore,additive effects of the drugs were observed.Immunoblot analysis showed that sorafenib and sunitib,but not erlotinib,efficiently blocked activation of the AKT pathway,while all three drugs displayed little effect on phosphorylation of ERK1/2.Cells treated with sorafenib or sunitinib expressed less interleukin-6 mRNA as well as less collagen type 1 mRNA and protein.Sorafenib was the only drug that also upregulated the expression of matrix metalloproteinase-2 and reduced the secretion of TGF-β1 protein.All three drugs showed insignificant or discordant effects on the mRNA and protein levels ofα-SMA.CONCLUSION:The tested SMI,especially sorafenib,exert inhibitory effects on activated PSC,which should be further evaluated in preclinical studies. AIM: To study if three clinically available small molecule kinase inhibitors (SMI), erlotinib, sunitinib and sorafenib, exert antifibrogenic effects on pancreatic stellate cells (PSC) and analyze the basis of their action. METHODS: Cultured rat PSC were exposed to SMI. Cell proliferation and viability were assayed by 5-bromo-2'-deoxyuridine incorporation assay and flow cytometry, respectively.2- Deoxy-2- [18F] fluoroglucose (18F- FDG) uptake was measured to study metabolic activity. Inhibition of the myofibroblastic PSC phenotype was monitored by immunofluorescence analysis of α-smooth muscle actin (α-SMA) expression. Levels of mRNAs were determined by real-time PCR, while protein expression and phosphorylation were analyzed by immunoblotting. Transforming growth factor-β1 levels in culture supernatants were quantified by ELISA .RESULTS: All three SMI inhibited cell proliferation and18F-FDG uptake in a dose-dependent manner and without significant cytotoxic effects. Fluorrthermore, additive effector cts of the drugs were observed. Immunoblot analysis showed that sorafenib and sunitib, but not erlotinib, efficiently blocked activation of the AKT pathway, while all three drugs displayed little effect on phosphorylation of ERK1 / 2.Cells treated with sorafenib or sunitinib expressed less interleukin -6 mRNA as well as less collagen type 1 mRNA and protein. Sorafenib was the only drug that also upregulated the expression of matrix metalloproteinase-2 and reduced the secretion of TGF-β1 protein. All three drugs showed insignificant or discordant effects on the mRNA and protein levels of α-SMA. CONCLUSION: The tested SMI, especially sorafenib, exert inhibitory effects on activated PSC, which should be further evaluated in preclinical studies.
其他文献
6月8日~9日,中国发展·潍坊2010——生物医药创新发展论坛在潍坊举办。此次论坛由中国致公党中央委员会主办,致公党山东省委员会、潍坊市人民政府承办,山东省科学技术厅、山东
TOP 01佳能IXUS 95 IS佳能IXUS 95 IS具有炫彩金属机身,搭载DIGIC 4影像处理器,在数据处理的速度和精度方面都有了明显的提升;“智慧AUTO”智能场景识别模式也增强了易用性。
位于卡尔斯鲁厄(Karlsruher)的 ZZ-Antriebe 公司专为工件及设备组件能够快速准确地调节定位开发了 ZZ-Servolift 系列减速机产品。该减速机在设计生产时大量采用了 Findling
A new one-dimensional polymeric complex [Cd(SCN)2(H2O)]L (L = N,N?-bis(furan- 2-ylmethylene)hydrazine) has been synthesized and characterized by IR, UV spectra,
TOP 01索尼HDR-CX100E外观设计小巧紧凑的索尼HDR-CX100E是面向家用市场的机型,主要针对入门初级用户,配备有10倍光学变焦的卡尔蔡司镜头,可满足拍摄1080i的高清视频的需要,
任何话语都是在语境中产生的。语境在交际和话语理解中发挥着重要的作用,本文基于一些典型实例着重探讨语境的三种基本功能:解释功能、限制功能和筛选功能。 Any discourse
Tamoxifen inducible cre-loxp system has been employed as a very powerful tool for cardiology research in mice. It enables researchers to control their intereste
1 事故经过 我厂3号发电机为东方电机厂生产的QFSN-200-2型机组,1992年投运。 1 accident after I plant on the 3rd generator for the East Motor Factory production QF
The twisted aromatics, functional dibenzo[d,f][1,3]dioxepine derivatives were synthesized in high yields from reactions of 5,5′-dibromo-2,2′-biphenol with cor
国家民委副主任吴仕民10月19日在京会见了以越南民族事务委员会副主席何雄为团长的越南代表团一行。吴仕民副主任向代表团介绍了我国民族工作部门以及民族工作的基本情况。他