Modulation of the Rho/ROCK pathway in heart and lung after thorax irradiation reveals targets to improve normal tissue toxicity.
Details
Serval ID
serval:BIB_D79A0DBB7AEE
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Modulation of the Rho/ROCK pathway in heart and lung after thorax irradiation reveals targets to improve normal tissue toxicity.
Journal
Current drug targets
ISSN
1873-5592 (Electronic)
ISSN-L
1389-4501
Publication state
Published
Issued date
11/2010
Peer-reviewed
Oui
Volume
11
Number
11
Pages
1395-1404
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Abstract
The medical options available to prevent or treat radiation-induced injury are scarce and developing effective countermeasures is still an open research field. In addition, more than half of cancer patients are treated with radiation therapy, which displays a high antitumor efficacy but can cause, albeit rarely, disabling long-term toxicities including radiation fibrosis. Progress has been made in the definition of molecular pathways associated with normal tissue toxicity that suggest potentially effective therapeutic targets. Targeting the Rho/ROCK pathway seems a promising anti-fibrotic approach, at least in the gut; the current study was performed to assess whether this target was relevant to the prevention and/or treatment of injury to the main thoracic organs, namely heart and lungs. First, we showed activation of two important fibrogenic pathways (Smad and Rho/ROCK) in response to radiation-exposure to adult cardiomyocytes; we extended these observations in vivo to the heart and lungs of mice, 15 and 30 weeks post-irradiation. We correlated this fibrogenic molecular imprint with alteration of heart physiology and long-term remodelling of pulmonary and cardiac histological structures. Lastly, cardiac and pulmonary radiation injury and bleomycin-induced pulmonary fibrosis were successfully modulated using Rho/ROCK inhibitors (statins and Y-27632) and this was associated with a normalization of fibrogenic markers. In conclusion, the present paper shows for the first time, activation of Rho/ROCK and Smad pathways in pulmonary and cardiac radiation-induced delayed injury. Our findings thereby reveal a safe and efficient therapeutic opportunity for the abrogation of late thoracic radiation injury, potentially usable either before or after radiation exposure; this approach is especially attractive in (1) the radiation oncology setting, as it does not interfere with prior anti-cancer treatment and in (2) radioprotection, as applicable to the treatment of established radiation injury, for example in the case of radiation accidents or acts of terrorism.
Keywords
Amides/pharmacology, Animals, Bleomycin/pharmacology, Connective Tissue Growth Factor/genetics, Connective Tissue Growth Factor/metabolism, Cytoskeleton/metabolism, Cytoskeleton/pathology, Endomyocardial Fibrosis/metabolism, Endomyocardial Fibrosis/prevention & control, Female, Heart/drug effects, Heart/physiopathology, Heart/radiation effects, Lung/drug effects, Lung/metabolism, Lung/pathology, Lung/radiation effects, Mice, Mice, Inbred C57BL, Myocytes, Cardiac/metabolism, Myocytes, Cardiac/pathology, Myocytes, Cardiac/radiation effects, Pravastatin/pharmacology, Protein Kinase Inhibitors/pharmacology, Protein-Serine-Threonine Kinases/genetics, Protein-Serine-Threonine Kinases/metabolism, Pyridines/pharmacology, Radiation Injuries/metabolism, Radiation Injuries/prevention & control, Radiation Pneumonitis/metabolism, Radiation Pneumonitis/prevention & control, Receptors, Transforming Growth Factor beta/genetics, Receptors, Transforming Growth Factor beta/metabolism, Simvastatin/pharmacology, Smad Proteins/genetics, Smad Proteins/metabolism, Thorax/radiation effects, rho-Associated Kinases/antagonists & inhibitors, rho-Associated Kinases/genetics, rho-Associated Kinases/metabolism, rhoB GTP-Binding Protein/genetics, rhoB GTP-Binding Protein/metabolism
Pubmed
Web of science
Create date
30/04/2018 16:03
Last modification date
20/08/2019 16:57