Abstract
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.
Highlights
Patients receiving thoracic irradiation for the treatment of lung, breast, or hematologic malignancies are prone to suffer from normal tissue toxicity [1]
As expected, increased SA-betagal activities were detected in epithelial cells of larger bronchi in lungs after whole thorax irradiation (WTI) compared to control lung sections
Induction of senescence was further confirmed by quantifying the cellular senescence mediator cyclin-dependent kinase inhibitor 1 (Cdkn1a/p21) on protein level by Western blot and on mRNA level by qRT-PCR (Figure 1C,D) as well as the cell cycle effector Ccnd1
Summary
Patients receiving thoracic irradiation for the treatment of lung, breast, or hematologic malignancies are prone to suffer from normal tissue toxicity [1]. A central response following diverse stressors, including ionizing radiation results in physiological dysfunction, in lungs is cellular senescence [6,7,8,9]. This permanent cell cycle arrest bears marked morphological as well as characteristic gene expression alterations. Agents that modulate the expression of constituents of the SASP, so-called SASP inhibitors or senomorphic drugs, have the potential to alleviate aging and associated diseased phenotypes, including cellular senescence [16] Radioprotection of the normal tissue via senescence and/or SASP-related signaling modulation without simultaneous protection or preferable radiosensitization of tumor tissue have important implications in oncology because higher doses of radiation might improve both local control and survival
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