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
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
Author(s)
Monceau V., Pasinetti N., Schupp C., Pouzoulet F., Opolon P., Vozenin M.C.
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
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 15:03
Last modification date
20/08/2019 15:57
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