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Carboxyamidotriazole alleviates muscle atrophy in tumor-bearing mice by inhibiting NF-κB and activating SIRT1

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Abstract

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-κB signaling, downregulated the level of TNF-α in muscle and both TNF-α 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.

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Abbreviations

CAI:

Carboxyamidotriazole

DMSO:

Dimethyl sulfoxide

FoxO:

Forkhead box O

IL-6:

Interleukin-6

MuRF1:

Muscle-specific RING-finger 1

PEG400:

Polyethylene glycol 400

PGC-1α:

Peroxisome proliferator-activated receptor-γ co-activator-1α

SIRT1:

Silent mating type information regulation 2 homolog 1

TNF-α:

Tumor necrosis factor-α

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Authors and Affiliations

  1. Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China

    Chen Chen, Rui Ju, Lei Zhu, Juan Li, Wei Chen, De-chang Zhang, Cai-ying Ye & Lei Guo

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  1. Chen Chen
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  2. Rui Ju
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  3. Lei Zhu
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  4. Juan Li
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  5. Wei Chen
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  6. De-chang Zhang
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  7. Cai-ying Ye
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  8. Lei Guo
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Corresponding author

Correspondence to Lei Guo.

Ethics declarations

This study is supported by Major Scientific and Technological Special Project 2014ZX09507003-003 (Ministry of Science and Technology, China), National Science Foundation of China 81402943, and PUMC Youth Fund (33320140046 and 3332015168).

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The authors declare that they have no competing interests..

Human and animal rights and informed consent

All animal manipulations were approved by the Institutional Animal Care and Use Committee of Peking Union Medical College.

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Chen, C., Ju, R., Zhu, L. et al. Carboxyamidotriazole alleviates muscle atrophy in tumor-bearing mice by inhibiting NF-κB and activating SIRT1. Naunyn-Schmiedeberg's Arch Pharmacol 390, 423–433 (2017). https://doi.org/10.1007/s00210-017-1345-8

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