The novel HDAC inhibitor NDACI054 sensitizes human cancer cells to radiotherapy |
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Authors: | Stephanie Hehlgans Katja Storch Inga Lange Nils Cordes |
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Affiliation: | 1. OncoRay – National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Germany;2. Department of Radiotherapy and Oncology, University of Frankfurt, Germany;3. Department of Radiation Oncology, University Hospital and Medical Faculty Carl Gustav Carus, Dresden University of Technology, Germany |
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Abstract: | Background and purposeInhibition of histone deacetylases (HDACs) has preclinically and clinically shown promise to overcome radio- and chemoresistance of tumor cells. NDACI054 is a novel HDAC inhibitor, which has been evaluated here for its effects on cell survival and radiosensitization of human tumor cell lines from different origins cultured under more physiological three-dimensional (3D), extracellular matrix (ECM)-based conditions.Material and methodsA549 lung, DLD-1 colorectal, MiaPaCa2 pancreatic and UT-SCC15 head and neck squamous cell carcinoma cells were treated with increasing NDACI054 concentrations (0–50 nM, 24 h) either alone or in combination with X-rays (single dose, 0–6 Gy). Subsequently, 3D clonogenic cell survival, HDAC activity, histone H3 acetylation, apoptosis, residual DNA damage (γH2AX/p53BP1 foci assay 24 h post irradiation) and phosphorylation kinetics of Ataxia telangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK), Caspase-3 and Poly(ADP-ribose)-Polymerase 1 (PARP 1) cleavage were analyzed.ResultsNDACI054 potently decreased HDAC activity with concomitant increase in acetyl-histone H3 levels, mediated significant cytotoxicity and radiosensitization. These effects were accompanied by a significant increase of residual γH2AX/p53BP1-positive foci, slightly elevated levels of Caspase-3 and PARP 1 cleavage but no induction of apoptosis.ConclusionsOur data show potent antisurvival and radiosensitizing effects of the novel HDAC inhibitor NDACI054 encouraging further preclinical examinations on this compound for future clinical use. |
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Keywords: | HDAC inhibitor Ionizing radiation Cancer cell lines 3D cell culture DNA repair |
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