Aliskiren targets multiple systems to alleviate cancer cachexia.
To examine the effects of aliskiren, a small-molecule renin inhibitor, on cancer cachexia and to explore the underlying mechanisms. A cancer cachexia model was established by subcutaneously injecting C26 mouse colon carcinoma cells into isogenic BALB/c mice. Aliskiren was administered intragastrically [10 mg/kg body weight (BW)] on day 5 (as a preventive strategy, AP group) or on day 12 (as a therapeutic strategy, AT group) after C26 injection. Mice that received no C26 injection (healthy controls, HC group) or only C26 injection but not aliskiren (cancer, CA group) were used as controls. BW, tumor growth, whole body functions, and survival were monitored daily in half of the mice in each group, whereas serum, tumors, and gastrocnemius muscles were harvested from the other mice after sacrifice on day 20 for further analysis. Aliskiren significantly alleviated multiple cachexia‑associated symptoms, including BW loss, tumor burden, muscle wasting, muscular dysfunction, and shortened survival. On the molecular level, aliskiren antagonized cachexia‑induced activation of the renin‑angiotensin system (RAS), systematic and muscular inflammation, oxidative stress, and autophagy‑lysosome as well as ubiquitin‑proteasome stimulation. In addition, early administration of aliskiren before cachexia development (AP group) resulted in more robust effects in alleviating cachexia or targeting underlying mechanisms than administration after cachexia development (AT group). Aliskiren exhibited potent anti‑cachexia activities. These activities were achieved through the targeting of at least four mechanisms underlying cachexia development: RAS activation, increase in systematic inflammation, upregulation of oxidative stress, and stimulation of autophagy-lysosome pathway (ALP) and ubiquitin-proteasome pathway (UPP).
Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
Chaoyi
C
Wang
Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
Dunwei
D
Guo
Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
Qiang
Q
Wang
Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
Song
S
You
Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
Zhongpeng
Z
Qiao
Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
Yong
Y
Liu
Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
Hang
H
Dai
Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
Hua
H
Tang
D000577:Amides / Q000008:administration & dosage*; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002100:Cachexia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D005650:Fumarates / Q000008:administration & dosage*; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology; D009133:Muscular Atrophy / Q000188:drug therapy / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D012084:Renin-Angiotensin System / Q000187:drug effects; D000092502:Renin Inhibitors
D000577:Amides; D005650:Fumarates; D000092502:Renin Inhibitors; C446481:aliskiren