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 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-B inhibitor approved for the clinical use, which has been shown to be effective in preventing muscle wasting in different catabolic conditions. 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 anesthesia, on days 3, 4, 5 and 7 after tumor inoculation, while C26-bearing mice were weighted and sacrificed under anesthesia 12 days after tumor transplantation. NF-B 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-B DNA-binding activity in the skeletal muscle on day 7 after tumor 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-B DNA-binding activity in the AH-130 hosts 3 days after tumor 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 tumor-bearing animals. Regarding C26 bearing-mice, Bortezomib did not prevent as well body and muscle weight loss 12 days after tumor 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.

Effect of the specific proteasome inhibitor Bortezomib on cancer-related muscle wasting

PENNA, FABIO
Co-first
;
MINERO, Valerio Giacomo;COSTELLI, Paola;
2016

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 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-B inhibitor approved for the clinical use, which has been shown to be effective in preventing muscle wasting in different catabolic conditions. 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 anesthesia, on days 3, 4, 5 and 7 after tumor inoculation, while C26-bearing mice were weighted and sacrificed under anesthesia 12 days after tumor transplantation. NF-B 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-B DNA-binding activity in the skeletal muscle on day 7 after tumor 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-B DNA-binding activity in the AH-130 hosts 3 days after tumor 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 tumor-bearing animals. Regarding C26 bearing-mice, Bortezomib did not prevent as well body and muscle weight loss 12 days after tumor 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.
7
3
345
354
http://onlinelibrary.wiley.com/doi/10.1002/jcsm.12050/abstract
cachexia; muscle wasting; Proteasome inhibitors
F. Penna; A. Bonetto; Z. Aversa; V.G. Minero; F. Rossi Fanelli; P. Costelli; M. Muscaritoli
File in questo prodotto:
File Dimensione Formato  
JCSM_2015_2016.pdf

Accesso aperto

Descrizione: articolo principale
Tipo di file: PDF EDITORIALE
Dimensione 723.77 kB
Formato Adobe PDF
723.77 kB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1509390
Citazioni
  • ???jsp.display-item.citation.pmc??? 29
  • Scopus 46
  • ???jsp.display-item.citation.isi??? 45
social impact