期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 13, 页码 -出版社
MDPI
DOI: 10.3390/ijms22137064
关键词
radiotherapy; normal tissue toxicity; lung injury; pulmonary disease; premature senescence; senescence-associated secretory phenotype; metformin
资金
- DFG [GRK1739/2]
- BMBF [02NUK047D]
- Open Access Publication Fund of the University of Duisburg-Essen
Radiation-induced damage to normal lung tissue can be mitigated by inhibiting cellular senescence and SASP expression in lung epithelial cells, thereby reducing vascular dysfunction and extravasation of immune and tumor cells. Metformin treatment shows potential in protecting normal lung tissue from radiation-induced senescence and associated lung injury.
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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