联合Carfilzomib 与Z-VAD-FMK 对肿瘤恶病质的防治作用及其机制研究.docVIP

联合Carfilzomib与Z-VAD-FMK对肿瘤恶病质的防治作用及其机制研究 王 强1，李春红2，王朝义1，唐 华1* （400016 重庆市，重庆医科大学附属第一医院：胃肠外科1，肿瘤科2） ［摘要］ 目的 评价联合蛋白酶体抑制剂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，预防作用明显大于治疗作用。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。 ［关键词］肿瘤恶病质；Carfilzomib；Z-VAD-FMK；泛素蛋白酶体通路；凋亡通路 ［中图法分类号］R730.5 ［文献标志码］A Effects of combination carfilzomib with Z-VAD-FMK on prevention and treatment of cancer cachexia and its mechanism Wang Qiang1,Li Chunhong2,Wang Chaoyi 1, Tang Hua1* ( Department of Gastrointestinal Surgery1 and Department of Oncology 2，The First Affiliated Hospital of Chongqing Medical UniversityChongqing，400016, China) Abstract: objective To investigate effects of combination carfilzomib with Z-VAD-FMK on prevention and treatment of cancer cachexia and its mechanism . Methods Murine colon C26 adenocarcinoma cells were injected into subcutaneous of male BALB /c mice to induce cancer cachexia model ．Then Carfilzomib and Z-VAD-FMK were given at different time points, inclued administered alone and combination . Body weight ,Tumor mass ,the gastrocnemius muscle were accurately weighed and the volume of tumors were measured ,spontaneous activity and survival time were detected . mRNA and protein level of caspase3，MuRF1 and MAFbx were detected with qRT-PCR and Western blot，respectively．Results Combination 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 gastrocnemius MuRF1, MAFbx, caspase3 in gastrocnemius muscle ; combined effect is bet