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首页> 外文期刊>Journal of Cellular Physiology >Nexavar/Stivarga and Viagra Interact to Kill Tumor Cells
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Nexavar/Stivarga and Viagra Interact to Kill Tumor Cells

机译：多吉美/ Stivarga和伟哥交互杀死肿瘤细胞

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摘要

We determined whether the multi-kinase inhibitor sorafenib or its derivative regorafenib interacted with phosphodiesterase 5 (PDE5) inhibitors such as Viagra (sildenafil) to kill tumor cells. PDE5 and PDGFR/ were over-expressed in liver tumors compared to normal liver tissue. In multiple cell types in vitro sorafenib/regorafenib and PDE5 inhibitors interacted in a greater than additive fashion to cause tumor cell death, regardless of whether cells were grown in 10 or 100% human serum. Knock down of PDE5 or of PDGFR/ recapitulated the effects of the individual drugs. The drug combination increased ROS/RNS levels that were causal in cell killing. Inhibition of CD95/FADD/caspase 8 signaling suppressed drug combination toxicity. Knock down of ULK-1, Beclin1, or ATG5 suppressed drug combination lethality. The drug combination inactivated ERK, AKT, p70 S6K, and mTOR and activated JNK. The drug combination also reduced mTOR protein expression. Activation of ERK or AKT was modestly protective whereas re-expression of an activated mTOR protein or inhibition of JNK signaling almost abolished drug combination toxicity. Sildenafil and sorafenib/regorafenib interacted in vivo to suppress xenograft tumor growth using liver and colon cancer cells. From multiplex assays on tumor tissue and plasma, we discovered that increased FGF levels and ERBB1 and AKT phosphorylation were biomarkers that were directly associated with lower levels of cell killing by rafenib + sildenafil. Our data are now being translated into the clinic for further determination as to whether this drug combination is a useful anti-tumor therapy for solid tumor patients. J. Cell. Physiol. 230: 2281-2298, 2015. (c) 2015 Wiley Periodicals, Inc.
机译：我们确定是否multi-kinase抑制剂索拉非尼或其导数regorafenib与磷酸二酯酶5 (PDE5)抑制剂如伟哥(万艾可)杀死肿瘤细胞。在肝肿瘤与正常肝组织。在体外多种细胞类型大于添加剂的方式相互作用引起肿瘤细胞死亡,不管人类血清细胞生长在10到100%。PDE5或PDGFR /重现了影响个人的药物。ROS增加/ RNS水平组合因果关系在细胞杀死。CD95 / FADD /半胱天冬酶8信号抑制药物结合毒性。Beclin1或ATG5抑制药物的组合杀伤力。一种蛋白激酶,p70 S6K, mTOR和激活物。药物组合也减少mTOR蛋白质表达式。保护而激活的表达mTOR蛋白质或抑制物的信号几乎废除毒性药物组合。西地那非和索拉非尼/ regorafenib互动体内抑制异种移植肿瘤的生长肝脏和结肠癌细胞。在肿瘤组织和血浆化验,我们发现增加FGF ERBB1和AKT的水平磷酸化是生物标记与低水平的细胞直接相关杀死rafenib +西地那非。被翻译成进一步的诊所确定是否这种药物组合是一个有用的抗肿瘤治疗实体瘤病人。(c) 2015年威利期刊公司。

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