OSU-03012 and Viagra Treatment Inhibits the Activity of Multiple Chaperone Proteins and Disrupts the Blood-Brain Barrier: Implications for Anti-Cancer Therapies.
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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DOI：
10.1002/jcp.24977
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发表时间：
2015-08
影响因子：
5.6
通讯作者：
Dent P
中科院分区：
文献类型：
--
作者：
Booth L;Roberts JL;Tavallai M;Nourbakhsh A;Chuckalovcak J;Carter J;Poklepovic A;Dent P
我们检查了OSU-03012（也称为AR-12）与磷酸二酯酶5（PDE 5）抑制剂之间的相互作用，以确定伴侣葡萄糖调节蛋白（GRP 78）/BiP/HSPA 5在细胞反应中的作用。西地那非（万艾可）与OSU-03012的相互作用大于相加作用，可杀死干细胞样GBM细胞。用OSU-03012/西地那非处理细胞：消除了多种致癌生长因子受体和质膜药物外排泵的表达，并导致GRP 78和其他HSP 70和HSP 90家族伴侣蛋白快速降解。质膜受体和药物外排泵的表达减少依赖于增强的PERK-eIF 2 α-ATF 4-CHOP信号传导，并被GRP 78过表达阻断。在体内，OSU-03012/西地那非在杀死肿瘤细胞而不损伤正常组织方面比塞来昔布和西地那非治疗更有效，并同时降低了正常脑中ABCB 1和ABCG 2的表达。OSU-03012/西地那非联合用药与低浓度索拉非尼协同杀死肿瘤细胞，与拉帕替尼协同杀死ERBB 1过表达肿瘤细胞。在对OSU-03012/西地那非给药小鼠的血浆和人肿瘤组织进行的多重测定中，我们注意到uPA信号转导显著降低，并将FGF和JAK 1/2鉴定为可能抑制杀伤反应的反应生物标志物。抑制FGFR信号传导和JAK 1/2信号传导（程度较低）可显著增强OSU-03012/西地那非致死率。J.细胞。Physiol.230：1982-1998，2015.版权所有© 2015作者.细胞生理学杂志由Wiley Periodicals，Inc.出版。
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‐eIF2α‐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. © 2015 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.