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Hansel, C.* ; Barr, S.* ; Schemann, A.V.* ; Lauber, K. ; Hess J. ; Unger, K. ; Zitzelsberger, H. ; Jendrossek, V.* ; Klein, D.*

Metformin protects against radiation-induced acute effects by limiting senescence of bronchial-epithelial cells.

Int. J. Mol. Sci. 22:7064 (2021)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Radiation-induced damage to normal lung parenchyma remains a dose-limiting factor in thorax-associated radiotherapy (RT). Severe early and late complications with lungs can increase the risk of morbidity in cancer patients after RT. Herein, senescence of lung epithelial cells following RT-induced cellular stress, or more precisely the respective altered secretory profile, the senescence-associated secretory phenotype (SASP), was suggested as a central process for the initiation and progression of pneumonitis and pulmonary fibrosis. We previously reported that abrogation of certain aspects of the secretome of senescent lung cells, in particular, signaling inhibition of the SASP-factor Ccl2/Mcp1 mediated radioprotection especially by limiting endothelial dysfunction. Here, we investigated the therapeutic potential of a combined metformin treatment to protect normal lung tissue from RT-induced senescence and associated lung injury using a preclinical mouse model of radiation-induced pneumopathy. Metformin treatment efficiently limited RT-induced senescence and SASP expression levels, thereby limiting vascular dysfunctions, namely increased vascular permeability associated with increased extravasation of circulating immune and tumor cells early after irradiation (acute effects). Complementary in vitro studies using normal lung epithelial cell lines confirmed the senescence-limiting effect of metformin following RT finally resulting in radioprotection, while fostering RT-induced cellular stress of cultured malignant epithelial cells accounting for radiosensitization. The radioprotective action of metformin for normal lung tissue without simultaneous protection or preferable radiosensitization of tumor tissue might increase tumor control probabilities and survival because higher radiation doses could be used.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Lung Injury ; Metformin ; Normal Tissue Toxicity ; Premature Senes-cence ; Pulmonary Disease ; Radiotherapy ; Senescence-associated Secretory Phenotype; Dna-damage Response; Cellular Senescence; Up-regulation; Lung Injury; Metabolism; Ampk; Accumulation; Macrophages; Activation; Induction
Sprache englisch
Veröffentlichungsjahr 2021
HGF-Berichtsjahr 2021
ISSN (print) / ISBN 1661-6596
e-ISSN 1422-0067
Quellenangaben Band: 22, Heft: 13, Seiten: , Artikelnummer: 7064 Supplement: ,
Verlag MDPI
Verlagsort Basel
Begutachtungsstatus Peer reviewed
POF Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30203 - Molecular Targets and Therapies
Forschungsfeld(er) Radiation Sciences
PSP-Element(e) G-521800-001
G-501000-001
Förderungen Deutsche Forschungsgemeinschaft
Scopus ID 85108872847
PubMed ID 34209135
Erfassungsdatum 2021-07-16