蛋白酶体抑制剂调控癌性恶病质的实验研究

Study of the intervention of ubiquitin-proteasome pathway on inflammation response in experimental cancer cachexia

目的:探讨蛋白酶体抑制剂对恶病质小鼠炎症细胞因子的合成和调控作用。方法:采用C26结肠癌细胞接种小鼠皮下,诱导恶病质模型,每天监测小鼠体重、食物摄入量和肿瘤体积,于肿瘤接种后第6、9、12和15天,每天给予荷瘤鼠腹腔注射生理盐水和不同剂量的蛋白酶体抑制Bortezomib(0.1、0.5和1.0mg/kg),第16天处死小鼠,检测肿瘤组织NF-κB活性、IL-6以及血清IL-6和IL-10水平。结果:第16天时,生理盐水组出现显著的体重和去瘤体重的下降(P<0.01)、腓肠肌萎缩及附睾脂肪的降解(P<0.01),同时血清IL-6、IL-10和肿瘤组织IL-6水平显著升高(P<0.01)。Bortezomib不同程度地抑制了去瘤体重、腓肠肌和附睾脂肪的降解。Bortezomib剂量依赖性地抑制了肿瘤组织NF-κB的激活及IL-6的合成,以1.0mg/kg组最显著。0.5mg/kg组显著抑制了血清IL-6水平的升高(P<0.01)。0.5和1.0mg/kg组明显抑制肿瘤生长(P<0.01)。结论:蛋白酶体抑制剂通过抑制肿瘤组织NF-κB的激活,从而抑制癌性炎性反应和组织成分降解,改善恶病质。

Objective：To investigate the effect of Bortezomib （an inhibitor of proteasome） on IL-6 synthesis and cachexia in colon 26 tumor bearing mice. Methods： Murine colon 26 adenocarcinoma cells were inoculated subcutaneously in male BALB/c mice to induce cachexia. Saline and three doses of Bortezomib （0.1, 0.5 and 1.0 mg/kg） were given intraperitoneally on day 6, 9, 12 and 15 after tumor inoculation and mice were sacrificed on day 16. Body weight, food intake and tumor volume were monitored daily. Serum levels of IL-6 and IL-10, tumor tissue levels of IL-6 and activity of NF-κB in tumor tissues were investigated in all animals. Results：By day 16, saline treated tumor-bearing mice showed significant body weight and carcass weight changes （P0.01）, gastrocnemius muscle wasting and epididymal fat depletion （P0.01）. Furthermore, Tumor-bearing caused a significant increase of IL-6 and IL-10 （P0.01） in serum and IL-6 in tumor tissues. Administration of Bortezomib attenuated the wasting of carcass weight, gastrocnemius muscle and epididymal fat. Bortezomib dose dependently inhibited the NF-κB activation and IL-6 synthesis of the tumor cells, and the maximal inhibition was observed at the dose of 1.0 mg/kg （P0.01）. Bortezomib 0.5 mg/kg significantly inhibited the increase of serum IL-6 （P0.01）. Bortezomib showed significant anti-tumor effect, and tumor growth was significantly inhibited by Bortezomib with 0.5 and 1.0 mg/kg （P0.01）. Conclusion：Bortezomib can inhibit NF-κB activation, tissue wasting and cancer cachexia.