Amiloride ameliorates muscle wasting in cancer cachexia through inhibiting tumor-derived exosome release

Skeletal Muscle

Suheng Wang¹  Huiqin Zhuo²  Shiqin Li³  Lin Wang⁴  Ruohan Lu⁵  Lin Zhou⁵  Haisheng Liu⁵  Tong Zhang⁵  Donghai Lin⁶  Caihua Huang⁷  Qinxi Li⁸  Bin Jiang⁸  Wei Shao⁹ 

[1] Collaborative Innovation Center of Chemistry for Energy Materials, College of Chemistry and Chemical Engineering, Xiamen University, 361005, Xiamen, China;Department of Gastrointestinal Surgery, The Affiliated Zhongshan Hospital, Xiamen University, 361004, Xiamen, Fujian, China;Department of Medical Oncology, Xiang’an Hospital of Xiamen University, Xiamen, China;Department of Oncology, Institute of Gastrointestinal Oncology, Zhongshan Hospital, Xiamen University, 361004, Xiamen, China;Key Laboratory for Chemical Biology of Fujian Province, MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, College of Chemistry and Chemical Engineering, Xiamen University, 361005, Xiamen, China;Key Laboratory for Chemical Biology of Fujian Province, MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, College of Chemistry and Chemical Engineering, Xiamen University, 361005, Xiamen, China;High-field NMR Center, College of Chemistry and Chemical Engineering, Xiamen University, 361005, Xiamen, China;Research and Communication Center of Exercise and Health, Xiamen University of Technology, 361024, Xiamen, China;State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, 361102, Xiamen, China;Xiamen Cardiovascular Hospital, Xiamen University, 361000, Xiamen, China;

关键词: Amiloride;    Cancer cachexia;    Muscle wasting;    Exosome;    Exosome-release inhibition;   

DOI  :  10.1186/s13395-021-00274-5

来源: Springer

【 摘 要 】

BackgroundCancer cachexia (CAC) reduces patient survival and quality of life. Developments of efficient therapeutic strategies are required for the CAC treatments. This long-term process could be shortened by the drug-repositioning approach which exploits old drugs approved for non-cachexia disease. Amiloride, a diuretic drug, is clinically used for treatments of hypertension and edema due to heart failure. Here, we explored the effects of the amiloride treatment for ameliorating muscle wasting in murine models of cancer cachexia.MethodsThe CT26 and LLC tumor cells were subcutaneously injected into mice to induce colon cancer cachexia and lung cancer cachexia, respectively. Amiloride was intraperitoneally injected daily once tumors were formed. Cachexia features of the CT26 model and the LLC model were separately characterized by phenotypic, histopathologic and biochemical analyses. Plasma exosomes and muscle atrophy-related proteins were quantitatively analyzed. Integrative NMR-based metabolomic and transcriptomic analyses were conducted to identify significantly altered metabolic pathways and distinctly changed metabolism-related biological processes in gastrocnemius.ResultsThe CT26 and LLC cachexia models displayed prominent cachexia features including decreases in body weight, skeletal muscle, adipose tissue, and muscle strength. The amiloride treatment in tumor-bearing mice distinctly alleviated muscle atrophy and relieved cachexia-related features without affecting tumor growth. Both the CT26 and LLC cachexia mice showed increased plasma exosome densities which were largely derived from tumors. Significantly, the amiloride treatment inhibited tumor-derived exosome release, which did not obviously affect exosome secretion from non-neoplastic tissues or induce observable systemic toxicities in normal healthy mice. Integrative-omics revealed significant metabolic impairments in cachectic gastrocnemius, including promoted muscular catabolism, inhibited muscular protein synthesis, blocked glycolysis, and impeded ketone body oxidation. The amiloride treatment evidently improved the metabolic impairments in cachectic gastrocnemius.ConclusionsAmiloride ameliorates cachectic muscle wasting and alleviates cancer cachexia progression through inhibiting tumor-derived exosome release. Our results are beneficial to understanding the underlying molecular mechanisms, shedding light on the potentials of amiloride in cachexia therapy.

【 授权许可】

CC BY