ABSTRACT
The purpose of this study was to investigate the role of Sestrin2 in response to radiation-induced injury to the heart and on the cardiomyopathy development in the mouse. Mice with genetic deletion of the Sestrin2 (Sestrin2 knockout mice [Sestrin2 KO]) and treatment with irradiation (22 or 15 Gy) were used as independent approaches to determine the role of Sestrin2. Echocardiography (before and after isoproterenol challenge) and left ventricular (LV) catheterization were performed to evaluate changes in LV dimensions and function. Masson's trichrome was used to assess myocardial fibrosis. Immunohistochemistry and Western blot were used to detect the capillary density. After 22 or 15 Gy irradiation, the LV ejection fraction (EF) was impaired in wt mice at 1 week and 4 months after irradiation when compared with sham irradiation. Compared to wt mice, Sestrin2 KO mice had significant reduction in reduced LVEF at 1 week and 4 months after irradiation. A significant increase in LV end-diastolic pressure and myocardial fibrosis and a significant decrease in capillary density were observed in irradiation-wt mice, as well as in irradiation-Sestrin2 KO mice. Sestrin2 involved in the regulation of cardiomyopathy (such as myocardial fibrosis) after irradiation. Overexpression of Sestrin2 might be useful in limiting radiation-induced myocardial injury.
Subject(s)
Cardiomyopathies/etiology , Cardiomyopathies/metabolism , Myocardium/metabolism , Nuclear Proteins/metabolism , Radiation Injuries/etiology , Radiation Injuries/metabolism , Animals , Capillaries/metabolism , Capillaries/radiation effects , Cardiomyopathies/pathology , Cardiomyopathies/physiopathology , Fibrosis , Gene Knockout Techniques , Heart/physiopathology , Heart/radiation effects , Hemodynamics/radiation effects , Male , Mice , Mice, Inbred C57BL , Myocardium/pathology , Nuclear Proteins/deficiency , Nuclear Proteins/genetics , Peroxidases , Radiation Injuries/pathology , Radiation Injuries/physiopathology , Survival Analysis , Time Factors , Ventricular Function, Left/radiation effectsABSTRACT
The purpose of this study was to evaluate the radiation-enhancing effect of sodium glycididazole, and the corresponding mechanisms of action on laryngeal cancer cells. Two laryngeal cancer cell lines (Hep-2 and UT-SCC-19A) were irradiated with X-rays in the presence or absence of sodium glycididazole. Cell survival, DNA damage and repair, cell apoptosis, cell cycle distribution, expression of proteins related to cell cycle checkpoint, and apoptosis were measured. Significantly increased DNA damages, decreased cells in the G1 phase, arrested cells at G2/M phase, decreased DNA repair protein XRCC1 foci formation, and enhanced cell apoptosis were observed in laryngeal cell lines treated by sodium glycididazole combined with irradiation compared with the irradiation alone. The combined treatment downregulated the protein expressions of ataxia-telangiectasia mutated (ATM), p-ATM, CHK2, and P53 but upregulated the protein expressions of MDM2 and Cdk2. This study indicates that sodium glycididazole enhances the radiosensitivity of laryngeal cancer cells through downregulation of ATM signaling pathway in vitro and in vivo.
Subject(s)
Ataxia Telangiectasia Mutated Proteins/metabolism , Imidazoles/pharmacology , Laryngeal Neoplasms/metabolism , Radiation-Sensitizing Agents/pharmacology , Signal Transduction/drug effects , Animals , Apoptosis/drug effects , Biomarkers, Tumor/metabolism , Cell Cycle/drug effects , Cell Line, Tumor , Cell Survival/drug effects , DNA Repair/drug effects , Disease Models, Animal , Hep G2 Cells , Humans , Hypoxia/drug therapy , Hypoxia/metabolism , Laryngeal Neoplasms/pathology , Mice , Tumor Burden/drug effects , Tumor Burden/radiation effects , Xenograft Model Antitumor AssaysABSTRACT
The aim of this study was to investigate the effect of C-reactive protein (CRP) level on the prognosis of patients with locoregionally advanced laryngeal carcinoma treated with chemoradiotherapy. Fifty-seven patients with locoregionally advanced laryngeal carcinoma (cT3-4, N0-3, M0) treated with chemoradiotherapy were reviewed retrospectively. Chemoradiotherapy comprised external beam radiotherapy to the larynx (70 Gy) with three cycles of cisplatin at 3-week intervals. Elevated CRP was defined as >8 mg/L. The survival rate was calculated using the Kaplan-Meier method, and a multivariate analysis was used to identify significant factors associated with prognosis, using a Cox proportional hazards model. During the median (range) follow-up of 5 years (1.3-5), 29 patients died from laryngeal cancer; the 5-year cancer-specific survival (CSS) rate was 49.12%. Fifteen patients had a high CRP level before chemoradiotherapy (>8 mg/L), and their CSS rate was significantly worse than that in the remaining patients (P = 0.003). Multivariate analysis showed that CRP and tumor site were independent prognostic indicators for CSS, with a hazard ratio of 2.66 (95% confidence interval (CI), 1.22-5.82; P = 0.014) and a hazard ratio of 1.67 (95% CI, 1.01-2.77; P = 0.045), respectively. Of those with elevated CRP, the CRP levels of ten patients became normal after chemoradiotherapy, of whom four were alive with no evidence of recurrence or metastasis during the follow-up. By contrast, all six with no CRP normalization after chemoradiotherapy died within 3.8 years. The elevation of CRP before treatment predicts a poor prognosis in patients with locoregionally advanced laryngeal carcinoma treated with chemoradiotherapy.
