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首页> 外文期刊>Journal of Cellular Physiology >PDE5 Inhibitors Enhance Celecoxib Killing in Multiple Tumor Types
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PDE5 Inhibitors Enhance Celecoxib Killing in Multiple Tumor Types

机译：PDE5抑制剂提高塞来昔布的死亡多种肿瘤类型

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摘要

The present studies determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with a clinically relevant NSAID, celecoxib, to kill tumor cells. Celecoxib and PDE5 inhibitors interacted in a greater than additive fashion to kill multiple tumor cell types. Celecoxib and sildenafil killed ex vivo primary human glioma cells as well as their associated activated microglia. Knock down of PDE5 recapitulated the effects of PDE5 inhibitor treatment; the nitric oxide synthase inhibitor L-NAME suppressed drug combination toxicity. The effects of celecoxib were COX2 independent. Over-expression of c-FLIP-s or knock down of CD95/FADD significantly reduced killing by the drug combination. CD95 activation was dependent on nitric oxide and ceramide signaling. CD95 signaling activated the JNK pathway and inhibition of JNK suppressed cell killing. The drug combination inactivated mTOR and increased the levels of autophagy and knock down of Beclin1 or ATG5 strongly suppressed killing by the drug combination. The drug combination caused an ER stress response; knock down of IRE1/XBP1 enhanced killing whereas knock down of eIF2/ATF4/CHOP suppressed killing. Sildenafil and celecoxib treatment suppressed the growth of mammary tumors in vivo. Collectively our data demonstrate that clinically achievable concentrations of celecoxib and sildenafil have the potential to be a new therapeutic approach for cancer. J. Cell. Physiol. 230: 1115-1127, 2015. (c) 2014 Wiley Periodicals, Inc., A Wiley Company
机译：目前的临床研究确定有关磷酸二酯酶5抑制剂(PDE5)与临床相关的非甾体抗炎药,塞来昔布,杀死肿瘤细胞。在一个大于PDE5抑制剂相互作用添加剂的方式杀死多个肿瘤细胞类型。主要人类神经胶质瘤细胞以及它们的活化的小胶质细胞有关。PDE5重现PDE5抑制剂的影响治疗;L-NAME压制毒性的药物组合。塞来昔布是COX2独立的影响。超表达c-FLIP-s或击倒CD95 / FADD显著减少造成的药物的组合。一氧化氮和神经酰胺信号。物途径和信号激活抑制物抑制细胞死亡。灭活mTOR和增加药物组合自噬的水平和Beclin1击倒由药物或ATG5强烈抑制杀死组合。应激反应;杀死而击倒eIF2 / ATF4 /切抑制杀人。治疗抑制乳腺肿瘤的生长体内。临床可实现的塞来昔布的浓度和西地那非是一个新的有潜力针对癌症的治疗方法。杂志。230:1115 - 1127年,2015年。期刊,Inc .威利公司

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