Metformin protects against radiation-induced acute effects by limiting senescence of bronchial-epithelial cells.
Int. J. Mol. Sci. 22:7064 (2021)
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
Typ der Hochschulschrift
Herausgeber
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
Keywords plus
Sprache
englisch
Veröffentlichungsjahr
2021
Prepublished im Jahr
HGF-Berichtsjahr
2021
ISSN (print) / ISBN
1661-6596
e-ISSN
1422-0067
ISBN
Bandtitel
Konferenztitel
Konferzenzdatum
Konferenzort
Konferenzband
Quellenangaben
Band: 22,
Heft: 13,
Seiten: ,
Artikelnummer: 7064
Supplement: ,
Reihe
Verlag
MDPI
Verlagsort
Basel
Tag d. mündl. Prüfung
0000-00-00
Betreuer
Gutachter
Prüfer
Topic
Hochschule
Hochschulort
Fakultät
Veröffentlichungsdatum
0000-00-00
Anmeldedatum
0000-00-00
Anmelder/Inhaber
weitere Inhaber
Anmeldeland
Priorität
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
Copyright
Erfassungsdatum
2021-07-16