Carboxyamidotriazole alleviates muscle atrophy in tumor-bearing mice by inhibiting NF-κB and activating SIRT1
Carboxyamidotriazole alleviates muscle atrophy in tumor-bearing mice by inhibiting NF-κB and activating SIRT1
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羧酰胺三唑通过抑制 NF-κ B 和激活 SIRT1 减轻荷瘤小鼠的肌肉萎缩
DOI：
10.1007/s00210-017-1345-8
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发表时间：
2017-04-01
影响因子：
3.6
通讯作者：
Guo, Lei
中科院分区：
文献类型：
--
作者：
Chen, Chen;Ju, Rui;Guo, Lei
癌症恶病质是一种以炎症反应为特征的复杂疾病，与癌症患者的体力状态差和死亡率高有关。羧氨基三唑（CAI）是一种无细胞毒性的化疗药物，在许多疾病的治疗中显示出抗炎作用。在这里，我们研究了CAI对晚期刘易斯肺癌（LLC）小鼠肌肉损失的预防和治疗作用。从第19天至研究结束，CAI给药小鼠的胴体重量显著高于溶媒组小鼠。腓肠肌和附睾脂肪组织重量也增加CAI治疗。其保护机制可能与以下几点有关：CAI处理通过降低肌肉特异性FoxO 3转录因子和泛素E3连接酶（MuRF 1和atrogin 1）的表达，抑制肌肉蛋白质的降解。CAI抑制NF-κ B B信号通路，下调肌肉中TNF-α水平和血清中TNF-α和IL-6水平，直接刺激SIRT 1活性，增加肌肉中SIRT 1含量。这些结果表明，CAI可以减轻肌肉萎缩，是一种很有前途的治疗肺癌恶病质的药物。
Cancer cachexia is a complex disorder characterized by inflammatory responses, and it is associated with poor performance status and high mortality rate of cancer patients. Carboxyamidotriazole (CAI), a noncytotoxic chemotherapy agent, shows anti-inflammatory features in the treatment of many diseases. Here, we investigated the preventive and therapeutic effects of CAI on muscle loss that occurred in mice with advanced Lewis lung carcinoma (LLC). The carcass weights of CAI-treated mice were significantly higher than that of mice in the vehicle group from Day 19 to the end of the study. The gastrocnemius and epididymal adipose tissue weights were also increased by CAI treatment. The protective mechanisms might be attributed to the following points: CAI treatment inhibited the proteolysis in muscles by decreasing expressions of muscle-specific FoxO3 transcription factor and ubiquitin E3 ligases (MuRF1 and atrogin1). Moreover, CAI restricted the NF-kappa B signaling, downregulated the level of TNF-alpha in muscle and both TNF-alpha and IL-6 levels in serum, directly stimulated SIRT1 activity in vitro, and increased SIRT1 content in muscle. These results indicate that CAI can alleviate muscle wasting and is a promising drug against lung cancer cachexia.