Booth Laurence, Roberts Jane L, Cruickshanks Nichola, Tavallai Seyedmehrad, Webb Timothy, Samuel Peter, Conley Adam, Binion Brittany, Young Harold F, Poklepovic Andrew, Spiegel Sarah, Dent Paul
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia.
J Cell Physiol. 2015 May;230(5):1115-27. doi: 10.1002/jcp.24843.
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 IRE1α/XBP1 enhanced killing whereas knock down of eIF2α/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.
本研究确定了临床上相关的磷酸二酯酶5（PDE5）抑制剂是否与临床上相关的非甾体抗炎药塞来昔布相互作用以杀死肿瘤细胞。塞来昔布和PDE5抑制剂以大于相加的方式相互作用以杀死多种肿瘤细胞类型。塞来昔布和西地那非可杀死体外原发性人胶质瘤细胞及其相关的活化小胶质细胞。敲低PDE5可重现PDE5抑制剂治疗的效果；一氧化氮合酶抑制剂L-NAME可抑制药物联合毒性。塞来昔布的作用不依赖于COX2。c-FLIP-s的过表达或CD95/FADD的敲低可显著降低药物联合的杀伤作用。CD95激活依赖于一氧化氮和神经酰胺信号传导。CD95信号传导激活JNK途径，抑制JNK可抑制细胞杀伤。药物联合可使mTOR失活并增加自噬水平，敲低Beclin1或ATG5可强烈抑制药物联合的杀伤作用。药物联合可引起内质网应激反应；敲低IRE1α/XBP1可增强杀伤作用，而敲低eIF2α/ATF4/CHOP可抑制杀伤作用。西地那非和塞来昔布治疗可抑制体内乳腺肿瘤的生长。总体而言，我们的数据表明，临床上可达到的塞来昔布和西地那非浓度有可能成为一种新的癌症治疗方法。
