Results 1 - 10 of 3970
Results 1 - 10 of 3970. Search took: 0.023 seconds
|Sort by: date | relevance|
[en] The p53 oncosuppressor is very seldom mutated in neuroblastoma, but several mechanisms cooperate to its functional inactivation in this tumor. Increased MDM2 levels, due to genetic amplification or constitutive inhibition of p14ARF, significantly contribute to this event highlighting p53 reactivation as an attractive perspective for neuroblastoma treatment. In addition to its role in tumorigenesis, MYCN sensitizes untransformed and cancer cells to apoptosis. This is associated to a fine modulation of the MDM2–p53 pathway. Indeed MYCN induces p53 and MDM2 transcription, and, by evoking a DNA damage response (DDR), it stabilizes p53 and its proapoptotic kinase Homeodomain Interacting Protein Kinase 2 (HIPK2). Through the regulation of the HIPK2-p53 inhibitor High Mobility Group protein A1 (HMGA1) and the homeobox proteins BMI-1 and TWIST-1, MYCN establishes a delicate balance between pro- and antiapoptotic molecules that might be easily perturbed by a variety of insults, leading to cell death. MDM2–p53 antagonists, such as Nutlin-3, are strikingly prone to inducing death in MYCN-amplified neuroblastoma, by further pushing on HIPK2 accumulation. Here we discuss implications and caveats of exploiting this pathway and its connections to MYCN-induced DDR for a tailored therapy of MYCN-amplified neuroblastoma.
[en] Hyperthermia (HT) acts as a cancer treatment by direct cell killing, radiosensitization, and promotion of tumor reoxygenation. The sensor proteins of the DNA damage response (DDR) are the direct targets of HT. However, the spatiotemporal properties of sensor proteins under HT are still unclear. Therefore, investigating the impact of HT on sensor proteins is of great importance. In the present study, the human fibrosarcoma cell line HT1080 stably transfected with 53BP1-GFP [the DDR protein 53BP1 fused to green fluorescent protein (GFP)] was used to investigate the real-time cellular response to DNA double-strand breaks (DSBs) induced by γ-rays. Using live-cell imaging combined with HT treatment, the spatiotemporal properties of the 53BP1 protein were directly monitored and quantitatively studied. We found that HT could delay and decrease the formation of 53BP1 ionizing radiation–induced foci (IRIF). Moreover, through the in situ tracking of individual IRIF, it was found that HT resulted in more unrepaired IRIF over the period of observation compared with IR alone. Additionally, the unrepaired IRIF had a larger area, higher intensity, and slower repair rate. Indeed, almost every cell treated with HT had unrepaired IRIF, and the majority of these IRIF increased in area individually, while the rest increased in area by the merging of adjacent IRIF. In summary, our study demonstrated that HT could perturb the primary event in the DDR induced by IR, and this may have important implications for cancer treatment and heat radiosensitization.
[en] Recent research shows that extra-nuclear cell-free chromatin (cfCh) released from dying cells can freely enter into healthy cells and integrate into their genomes. Genomic integration of cfCh leads to dsDNA breaks and activation of inflammatory cytokines both of which occur concurrently with similar kinetics and that induction of inflammation can be abrogated by preventing DNA breaks with the use of cfCh inactivating agents. The proposal is put forward that inflammatory cytokines are a new family of DDR proteins that are activated following dsDNA breaks inflicted by genomic integration of cfCh.
[en] Background and purpose: In muscle-invasive bladder cancer there is an urgent need to identify relatively non-toxic radiosensitising agents for use in elderly patients. Histone deacetylase inhibitors radiosensitise tumour cells but not normal cells in vitro and variously downregulate DNA damage signalling, homologous recombination (HR) and non-homologous end-joining (NHEJ) repair proteins. We investigated panobinostat (PAN) as a potential radiosensitiser in bladder cancer cells. Materials and methods: Clonogenic assays were performed in RT112 bladder cancer cells, and RT112 cells stably knocked down for RAD51 or Ku80 by shRNAi. Resolution of γH2AX foci was determined by immunofluorescence confocal microscopy, cell cycle progression by FACS analysis and protein expression by western blotting. Results: PAN had a greater radiosensitising effect in Ku80KD than RT112 or RAD51KD cells; enhancement ratios 1.35 for Ku80KD at 10 nM (IC20 for Ku80KD) and 1.31 for RT112 and RAD51KD at 25 nM (IC40 for both). PAN downregulated MRE11, NBS1 and RAD51, but not Ku70 and Ku80, increased γH2AX foci formation in a dose-dependent manner and delayed γH2AX foci repair after ionising radiation. Conclusions: PAN acts as a radiosensitiser in bladder cancer cell lines, and appears to target HR rather than NHEJ. As muscle-invasive bladder tumours have reduced Ku-DNA binding, PAN could be particularly useful as a radiosensitiser in bladder cancer
[en] Background and purpose: To evaluate the impact of ATR inhibition using AZD6738 in combination with radiotherapy on the response of non-small cell lung cancer (NSCLC) tumour models and a murine model of radiation induced fibrosis.
[en] In photochemotherapy, ultraviolet radiation (UVR: 280-400 nm) or visible light is combined with a photosensitizing drug to produce a therapeutic effect. Importantly, the beneficial impact of photochemotherapy is not achieved by the drug or radiation alone. It is a proven therapeutic strategy for a number of non-malignant hyper proliferative skin conditions and various cancers. All existing photochemotherapies have drawbacks - for example the association of (psoralen plus UVA) PUVA with the development of skin cancer, and pain that is often associated with photodynamic therapy (PDT) treatment of skin lesions. In this study, we explored an alternate possibility to address this need by exploiting coralyne-mediated DNA photo-sensitisation to low and non-toxic doses of UVA radiation. Current investigation also illustrates an overview of the mechanism of action underlying coralyne mediated photosensitization of cancer cells. (author)
[en] Radiotherapy is a standard treatment for the solid tumors in cancer patients, which is often restricted by its high dose related toxicity to normal tissue and development of therapeutic resistance in cancer cells. We observed a preferential radiosensitizing effects of a small molecule, silibinin in invitro and pre-clinical tumor xenograft models of prostate cancer. Results are encouraging and reveal that the desired tumor growth inhibition can be achieved at lower doses of radiation treatment when it is combined with silibinin given orally. Various parameters including cell cycle, DNA damage and apoptosis were measured. Importantly, silibinin exhibited preferential radiosensitization of cancer cells and protected normal cells and tissues including various hematopoietic parameters from radiation-induced toxicities. Radiosensitization mechanism involved inhibition of nuclear translocation of EGFR and DNA-PK, indicating its effect on DNA repair signaling. The silibinin concentration used in this study can be physiologically achievable in patients which underlines the translational significance of this study for the radiotherapy for prostate cancer patients. (author)
[en] A study was carried out to detect the chemical change that might occur in irradiated orange and spice. Oxidative DNA damage can induce the production of 8-hydroxydeoxyguanine (8-OHdG) and thus the level of 8-hydroxydeoxyguanine was investigated using enzyme linked immunosorbent assay (ELISA) in the irradiated orange and spice which was compared with the unirradiated samples. By the difference in the oxidized guanine level that produce 8-hydroxydeoxyguanine in the irradiated and unirradiated samples, it can be clearly understood that detection of irradiated orange and spice is possible using monoclonal antibody for 8-hydroxydeoxyguanine in the ELAISA assay.(author)
[en] Sir2 maintains genomic stability in multiple ways in yeast. As a NAD+-dependent histone deacetylase, Sir2 has been reported to control chromatin silencing. In both budding yeast and Drosophila, overexpression of Sir2 extends life span. Previous reports have also demonstrated that Sir2 participate at DNA damage repair. A protein complex containing Sir2 has been reported to translocate to DNA double-strand breaks. Following DNA damage response, SIRT1 deacetylates p53 protein and attenuates its ability as a transcription factor. Consequently, SIRT1 over-expression increases cell survival under DNA damage inducing conditions. These previous observations mean a possibility that signals generated during the process of DNA repair are delivered through SIRT1 to acetylated p53. We present herein functional evidence for the involvement of SIRT1 in DNA repair response to radiation. In addition, this modulation of DNA repair activity may be connected to deacetylation of MRN proteins