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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
Korrespondenzautor
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
ISSN (print) / ISBN 1422-0067
e-ISSN 1661-6596
Zeitschrift International Journal of Molecular Sciences
Quellenangaben Band: 22, Heft: 13, Seiten: , Artikelnummer: 7064 Supplement: ,
Verlag MDPI
Verlagsort Basel
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) CCG Personalized Radiotherapy in Head and Neck Cancer (KKG-KRT)
Translational Metabolic Oncology (TMO)
Förderungen Deutsche Forschungsgemeinschaft