Antitumoral行动的抗肥胖药物奥利司他(XenicalTM)在乳腺癌细胞:细胞周期进程的封锁,促进凋亡细胞死亡和PEA3-mediated转录镇压Her2 / neu (erbB-2)致癌基因。
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梅内德斯杰,Vellon L,卢普R
Antitumoral行动的抗肥胖药物奥利司他(XenicalTM)在乳腺癌细胞:细胞周期进程的封锁,促进凋亡细胞死亡和PEA3-mediated转录镇压Her2 / neu (erbB-2)致癌基因。
安8月杂志。2005;16 (8):1253 - 67。2005年5月3日Epub。
- PubMed ID
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15870086 (在PubMed]
- 文摘
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背景:奥利司他(Xenicaltrade马克),美国食品和药物管理局(FDA)批准的药物对体重损失,最近被证明表现出抗肿瘤特性对前列腺癌细胞的能力阻止脂肪生成的脂肪酸合酶(FAS)的活性。FAS(致癌抗原- 519)上调约50%的乳腺癌,是预后不良的指标,最近与Her2 / neubeplayapp相关功能(erbB-2)致癌基因。材料与方法:我们评估了antitumoral奥利司他的影响对人类乳腺癌细胞系SK-Br3体外范式的FAS和Her2 / neu超表达在乳腺癌。结果:细胞周期分析显示,微摩尔的奥利司他诱导的浓度,以时间和剂量依赖性的方式显著变化在细胞群的分布包括一个完整的损失G2-M阶段,s阶段积累和相应增加在新兴sub-G1(凋亡)细胞。保利(ADP-ribose)聚合酶(PARP)解理,致力于细胞凋亡的早期事件所需细胞,更主要在orlistat-treated G1期细胞。当我们为特征的信号分子参与细胞事件后orlistat-induced抑制FAS活动和之前的抑制乳腺癌细胞增殖,大幅下调Her2 / neu-coded p185 (Her2 / neu)癌蛋白被发现在orlistat-treated SK-Br3细胞减少(> 90%)。有趣的是,一个重要的dna结合蛋白质积累PEA3, Ets转录因子家族中的一员,专门针对PEA3-binding图案出现在Her2 / neu基因启动子和下调其活动,在orlistat-treated SK-Br3细胞。当一个荧光素酶报告基因的Her2 / neu启动子在SK-Br3暂时性的转染细胞,奥利司他接触被发现显著抑制Her2 / neu基因的启动子活性,而Her2 / neu发起人轴承突变绑定DNA序列被奥利司他不受消极监管,从而证明完整PEA3结合位点的Her2 / neu orlistat-induced所需的启动子是转录镇压Her2 / neu超表达。核糖核酸干扰(RNAi)介导的基因表达沉默的FAS同样压抑的Her2 / neu PEA3-dependent方式基因表达,从而排除角色non-FAS orlistat-mediated效果。当奥利司他和anti-Her2 / neu抗体曲妥珠单抗(Herceptintrade马克)并发(奥利司他+曲妥珠单抗)或顺序(奥利司他——>曲妥珠单抗; trastuzumab --> orlistat) schedules was tested for synergism, addition or antagonism using the combination index (CI) method of Chou-Talalay, co-exposure of orlistat and trastuzumab demonstrated strong synergistic effects (CI10-90 = 0.110-0.847), whereas sequential exposure to orlistat followed by trastuzumab (CI10-90 = 0.380-1.210) and trastuzumab followed by orlistat (CI10-90 = 0.605-1.278) mainly showed additive or antagonistic interactions. Indeed, orlistat-induced FAS inhibition synergistically promoted apoptotic cell death when concurrently combined with trastuzumab as determined by an ELISA for histone-associated DNA fragments. Importantly, the degree of FAS expression in a panel of human breast cancer cell lines was predictive of sensitivity to orlistat-induced anti-proliferative effects as determined by a MTT-based characterization of metabolically viable breast cancer cells. Moreover, hypersensitivity to orlistat-induced cytotoxicity was observed in MCF-7 breast cancer cells engineered to overexpress Her2/neu (MCF-7/Her2-18 cells), which exhibit a significant up-regulation of FAS expression and activity. CONCLUSIONS: These findings reveal that the development of more potent and/or bioavailable orlistat's variants targeting the lipogenic activity of FAS may open a novel therapeutic avenue for treating Her2/neu-overexpressing breast carcinomas.