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首页> 外文期刊>Journal of Cachexia, Sarcopenia and Muscle >Effect of the specific proteasome inhibitor bortezomib on cancer-related muscle wasting
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Effect of the specific proteasome inhibitor bortezomib on cancer-related muscle wasting

机译：特定蛋白酶体抑制剂硼替佐米对癌症相关肌肉消瘦的影响

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Abstract Background Muscle wasting, a prominent feature of cancer cachexia, is mainly caused by sustained protein hypercatabolism. The enhanced muscle protein degradation rates rely on the activity of different proteolytic systems, although the Adenosine triphosphate (ATP)-ubiquitin-proteasome-dependent pathway and autophagy have been shown to play a pivotal role. Bortezomib is a potent reversible and selective proteasome and NF-???oB inhibitor approved for the clinical use, which has been shown to be effective in preventing muscle wasting in different catabolic conditions. The aim of the present study has been to investigate whether pharmacological inhibition of proteasome by bortezomib may prevent skeletal muscle wasting in experimental cancer cachexia. Methods Cancer cachexia was induced in rats by intraperitoneal injection of Yoshida AH-130 ascites hepatoma cells and in mice by subcutaneous inoculation of C26 carcinoma cells. Animals were then further randomized to receive bortezomib. The AH-130 hosts were weighted and sacrificed under anaesthesia, on Days 3, 4, 5, and 7 after tumour inoculation, while C26-bearing mice were weighted and sacrificed under anaesthesia 12 days after tumour transplantation. NF-???oB and proteasome activation, MuRF1 and atrogin-1 mRNA expression and beclin-1 protein levels were evaluated in the gastrocnemius of controls and AH-130 hosts. Results Bortezomib administration in the AH-130 hosts, although able to reduce proteasome and NF-???oB DNA-binding activity in the skeletal muscle on Day 7 after tumour transplantation, did not prevent body weight loss and muscle wasting. In addition, bortezomib exerted a transient toxicity, as evidenced by the reduced food intake and by the increase in NF-???oB DNA-binding activity in the AH-130 hosts 3 days after tumour transplantation. Beclin-1 protein levels were increased by bortezomib treatment in Day 3 controls but were unchanged on both Days 3 and 7 in the AH-130 hosts, suggesting that an early compensatory induction of autophagy may exist in healthy but not in tumour-bearing animals. Regarding C26-bearing mice, bortezomib did not prevent as well body and muscle weight loss 12 days after tumour implantation. Conclusions The results obtained suggest that proteasome inhibition by bortezomib is not able to prevent muscle wasting in experimental cancer cachexia. Further studies are needed to address the issue whether a different dosage of bortezomib alone or in combination with other drugs modulating different molecular pathways may effectively prevent muscle wasting during cancer cachexia.
机译：摘要背景肌肉消瘦是癌症恶病质的主要特征，主要是由于持续的蛋白质过度分解代谢所致。尽管三磷酸腺苷（ATP）-泛素-蛋白酶体依赖性途径和自噬已显示出关键作用，但增强的肌肉蛋白质降解速率取决于不同蛋白水解系统的活性。硼替佐米是一种有效的可逆且选择性的蛋白酶体和NF-κB抑制剂，已批准用于临床，已证明可有效预防在不同分解代谢条件下的肌肉消瘦。本研究的目的是研究硼替佐米的药理学抑制是否可以预防实验性恶病质中骨骼肌的浪费。方法腹膜内注射吉田AH-130腹水肝癌细胞诱导大鼠恶病质，皮下接种C26癌细胞诱导小鼠恶病质。然后将动物进一步随机分配接受硼替佐米。在肿瘤接种后第3、4、5和7天，在麻醉下称重并处死AH-130宿主，而在肿瘤移植后12天在麻醉下称重并处死具有C26的小鼠。在对照组和AH-130宿主的腓肠肌中评估了NF-κB和蛋白酶体的活化，MuRF1和atrogin-1 mRNA的表达以及beclin-1蛋白的水平。结果在AH-130宿主中施用硼替佐米，尽管能够在肿瘤移植后第7天降低骨骼肌中的蛋白酶体和NF-κBDNA结合活性，但不能防止体重减轻和肌肉消瘦。此外，硼替佐米具有短暂的毒性作用，这是由肿瘤移植后3天减少的食物摄入量和AH-130宿主中NF-κBDNA结合活性的增加所证实的。在第3天的对照组中，硼替佐米治疗可增加Beclin-1蛋白的水平，但在AH-130宿主中，第3天和第7天都没有改变，这表明健康的动物可能存在早期自噬的自噬诱导作用，而荷瘤动物则没有。对于携带C26的小鼠，硼替佐米不能在肿瘤植入后12天同时防止身体和肌肉的重量减轻。结论获得的结果表明硼替佐米抑制蛋白酶体不能预防实验性恶病质中的肌肉消耗。需要进一步研究以解决不同剂量的硼替佐米单独使用或与其他调节不同分子途径的药物联用可能有效预防癌症恶病质期间肌肉萎缩的问题。

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