Histone Deacetylase Inhibitors Sensitize Human Non-small Cell Lung Cancer Cells to Ionizing Radiation Through Acetyl p53-Mediated c-myc Down-Regulation

IntroductionHistone deacetylase inhibitors (HDACIs) induce growth arrest and apoptosis in cancer cells. In addition to their intrinsic anticancer properties, HDACIs modulate cellular responses to ionizing radiation (IR). We examined the molecular mechanism(s) associated with the radiosensitizing effects of HDACIs in human lung cancer cells.MethodsLung cancer cells were pretreated with the appropriate concentrations of suberoylanilide hydroxamic acid or trichostatin A. After 2 hours, cells were irradiated with various doses of γ-IR, and then we performed 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, fluorescence-activated cell sorting analysis, clonogenic assay, and Western blotting to detect cell viability or apoptosis and changes of specific proteins expression levels.ResultsIn this study, we showed that HDACIs (including suberoylanilide hydroxamic acid and trichostatin A) and IR synergistically trigger cell death in human non-small cell lung cancer cells. Cell viability and clonogenic survival were markedly decreased in cultures cotreated with HDACIs and IR. Interestingly, p53 acetylation at lysine 382 was significantly increased, and c-myc expression simultaneously down-regulated in cotreated cells. Radiosensitization by HDACIs was inhibited on transfection with small interfering RNA against p53 and c-myc overexpression, supporting the involvement of p53 and c-myc in this process. Furthermore, c-myc down-regulation and apoptotic cell death coinduced by IR and HDACI were suppressed in cells transfected with mutant K382R p53 and C135Y p53 displaying loss of acetylation at lysine 382 and DNA-binding activity, respectively.ConclusionsOur results collectively demonstrate that the degree of radiosensitization by HDACIs is influenced by acetyl p53-mediated c-myc down-regulation

Effect of general anaesthesia on functional outcome in patients with anterior circulation ischaemic stroke having endovascular thrombectomy versus standard care: a meta-analysis of individual patient data

Background: General anaesthesia (GA) during endovascular thrombectomy has been associated with worse patient outcomes in observational studies compared with patients treated without GA. We assessed functional outcome in ischaemic stroke patients with large vessel anterior circulation occlusion undergoing endovascular thrombectomy under GA, versus thrombectomy not under GA (with or without sedation) versus standard care (ie, no thrombectomy), stratified by the use of GA versus standard care. Methods: For this meta-analysis, patient-level data were pooled from all patients included in randomised trials in PuMed published between Jan 1, 2010, and May 31, 2017, that compared endovascular thrombectomy predominantly done with stent retrievers with standard care in anterior circulation ischaemic stroke patients (HERMES Collaboration). The primary outcome was functional outcome assessed by ordinal analysis of the modified Rankin scale (mRS) at 90 days in the GA and non-GA subgroups of patients treated with endovascular therapy versus those patients treated with standard care, adjusted for baseline prognostic variables. To account for between-trial variance we used mixed-effects modelling with a random effect for trials incorporated in all models. Bias was assessed using the Cochrane method. The meta-analysis was prospectively designed, but not registered. Findings: Seven trials were identified by our search; of 1764 patients included in these trials, 871 were allocated to endovascular thrombectomy and 893 were assigned standard care. After exclusion of 74 patients (72 did not undergo the procedure and two had missing data on anaesthetic strategy), 236 (30%) of 797 patients who had endovascular procedures were treated under GA. At baseline, patients receiving GA were younger and had a shorter delay between stroke onset and randomisation but they had similar pre-treatment clinical severity compared with patients who did not have GA. Endovascular thrombectomy improved functional outcome at 3 months both in patients who had GA (adjusted common odds ratio (cOR) 1·52, 95% CI 1·09–2·11, p=0·014) and in those who did not have GA (adjusted cOR 2·33, 95% CI 1·75–3·10, p<0·0001) versus standard care. However, outcomes were significantly better for patients who did not receive GA versus those who received GA (covariate-adjusted cOR 1·53, 95% CI 1·14–2·04, p=0·0044). The risk of bias and variability between studies was assessed to be low. Interpretation: Worse outcomes after endovascular thrombectomy were associated with GA, after adjustment for baseline prognostic variables. These data support avoidance of GA whenever possible. The procedure did, however, remain effective versus standard care in patients treated under GA, indicating that treatment should not be withheld in those who require anaesthesia for medical reasons