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首页> 外文期刊>Journal of Cellular Physiology >OSU-03012 and Viagra Treatment Inhibits the Activity of Multiple Chaperone Proteins and Disrupts the Blood-Brain Barrier: Implications for Anti-Cancer Therapies
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OSU-03012 and Viagra Treatment Inhibits the Activity of Multiple Chaperone Proteins and Disrupts the Blood-Brain Barrier: Implications for Anti-Cancer Therapies

机译：俄勒冈州立大学- 03012和伟哥治疗可以抑制多个伴护蛋白质和活动破坏血脑屏障:影响抗癌治疗

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We examined the interaction between OSU-03012 (also called AR-12) with phosphodiesterase 5 (PDE5) inhibitors to determine the role of the chaperone glucose-regulated protein (GRP78)/BiP/HSPA5 in the cellular response. Sildenafil (Viagra) interacted in a greater than additive fashion with OSU-03012 to kill stem-like GBM cells. Treatment of cells with OSU-03012/sildenafil: abolished the expression of multiple oncogenic growth factor receptors and plasma membrane drug efflux pumps and caused a rapid degradation of GRP78 and other HSP70 and HSP90 family chaperone proteins. Decreased expression of plasma membrane receptors and drug efflux pumps was dependent upon enhanced PERK-eIF2-ATF4-CHOP signaling and was blocked by GRP78 over-expression. In vivo OSU-03012/sildenafil was more efficacious than treatment with celecoxib and sildenafil at killing tumor cells without damaging normal tissues and in parallel reduced expression of ABCB1 and ABCG2 in the normal brain. The combination of OSU-03012/sildenafil synergized with low concentrations of sorafenib to kill tumor cells, and with lapatinib to kill ERBB1 over-expressing tumor cells. In multiplex assays on plasma and human tumor tissue from an OSU-03012/sildenafil treated mouse, we noted a profound reduction in uPA signaling and identified FGF and JAK1/2 as response biomarkers for potentially suppressing the killing response. Inhibition of FGFR signaling and to a lesser extent JAK1/2 signaling profoundly enhanced OSU-03012/sildenafil lethality. J. Cell. Physiol. 230: 1982-1998, 2015. (c) 2015 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.
机译：我们检查了俄勒冈州立大学- 03012之间的互动(也称为AR-12)与磷酸二酯酶5(PDE5抑制剂)决定的作用女伴glucose-regulated蛋白质(GRP78) /毕普HSPA5细胞反应。西地那非(伟哥)相互作用大于添加剂时尚与俄勒冈州立大学- 03012年杀死干细胞“绿带运动”细胞。俄勒冈州立大学- 03012 /西地那非:废除的表达多种肿瘤生长因子受体等离子体膜药物引起的射流泵和快速的GRP78和其他HSP70和退化一半的家庭伴侣蛋白的蛋白质。表达的质膜受体和药物射流泵是依靠增强PERK-eIF2-ATF4-CHOP信号和被GRP78的表达。俄勒冈州立大学- 03012 /西地那非是更有效的比塞来昔布治疗和西地那非杀死肿瘤细胞在不损害正常组织和并行的表达减少ABCB1 ABCG2在正常大脑。俄勒冈州立大学- 03012 /西地那非主体性的组合低浓度的索拉非尼杀死肿瘤细胞,拉帕替尼杀死ERBB1肿瘤细胞过度表达。在等离子体和人类的肿瘤组织俄勒冈州立大学- 03012 /西地那非治疗老鼠,我们注意到uPA信号和深刻的下降确定FGF生物标志物和JAK1/2响应潜在抑制死亡的反应。抑制FGFR信号和较小深刻程度JAK1/2信号增强俄勒冈州立大学- 03012 /西地那非致命性。230: 1982 - 1998, 2015。威利出版的细胞生理学杂志》上期刊、公司。

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