Carfilzomib联合Z-VAD-FMK对肿瘤恶病质的防治作用  

Effects of combination of carfilzomib and Z-VAD-FMK on prevention and treatment of in mice of cancer cachexia

作　　者：王强[1] 李春红[2] 王朝义[1] 唐华[1] 

机构地区：[1]重庆医科大学附属第一医院胃肠外科,重庆400016 [2]重庆医科大学附属第一医院肿瘤科,重庆400016

出　　处：《第三军医大学学报》2014年第22期2292-2295,共4页Journal of Third Military Medical University

摘　　要：目的评价联合运用蛋白酶体抑制剂Carfilzomib与Caspase抑制剂Z-VAD-FMK对肿瘤恶病质的防治作用及其机制。方法 BALB/c小鼠前腋皮下接种结肠腺癌C26细胞,建立肿瘤恶病质动物模型。随后在不同时间点给予Carfilzomib和Z-VAD-FMK单独与联合用药,检测荷瘤小鼠体质量、腓肠肌质量、肿瘤质量和体积、自发性生理活动和生存时间;qRT-PCR和Western blot检测腓肠肌Caspase3、MuRF1和MAFbx的mRNA表达水平和蛋白水平。结果 Carfilzomib与Z-VAD-FMK联合作用缓解荷瘤小鼠体质量下降,抑制骨骼肌萎缩和肿瘤生长,提高自发性生理活动和延长生存时间;减少腓肠肌MuRF1、MAFbx和Caspase3表达;联合作用大于单独用药(P<0.05),预防作用明显大于治疗作用(P<0.05)。结论 Carfilzomib与Z-VAD-FMK联合作用抑制了恶病质荷瘤小鼠腓肠肌泛素蛋白酶体通路和凋亡通路,可以预防和治疗肿瘤恶病质的发生、发展。Objective To investigate the effects of combination of carfilzomib and Caspase inhibitor Z-VAD-FMK on the prevention and treatment of cancer cachexia and its mechanism. Methods Murine colon adenocarcinoma cells（ C26 cells） were subcutaneously injected into male BALB / c mice to induce cancer cachexia model（ with typical cachexia signs and symptoms）. Then carfilzomib and Z-VAD-FMK in combination or alone were given at different time points. Body weight,tumor mass and volume,gastrocnemius muscle mass,spontaneous activity and survival time were detected. The mRNA and protein levels of Caspase 3,MuRF1 and MAFbx were detected with qRT-PCR and Western blotting,respectively. Results The combination of carfilzomib with Z-VAD-FMK could ameliorate weight loss in tumor-bearing mice,inhibit skeletal muscle atrophy and the growth of tumor,improve the spontaneous physiological activity,prolong the survival time and reduce the expression of MuRF1,MAFbx,and Caspase 3 in gastrocnemius muscle,showing better effects than carfilzomib or Z-VAD-FMK alone（ P〈0. 05）. The effects of prevention were better than that of treatment（ P〈 0. 05）. Conclusion Ubiquitin-proteasome pathway and apoptosis pathway are inhibited by the combination of carfilzomib and Z-VAD-FMK in cancer cachexia mice,indicating that the combination can prevent and treat the development of cancer cachexia.

关 键 词：肿瘤恶病质 carfilzomib Z-VAD-FMK 泛素蛋白酶体通路 凋亡通路 

分 类 号：R-332[医药卫生] R589.205