The novel HDAC inhibitor NDACI054 sensitizes human cancer cells to radiotherapy.
OBJECTIVE
Inhibition 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.


METHODS
A549 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 24h 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.


RESULTS
NDACI054 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.


CONCLUSIONS
Our data show potent antisurvival and radiosensitizing effects of the novel HDAC inhibitor NDACI054 encouraging further preclinical examinations on this compound for future clinical use.
OncoRay - National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Germany; Department of Radiotherapy and Oncology, University of Frankfurt, Germany.
Stephanie
S
Hehlgans
Katja
K
Storch
Inga
I
Lange
Nils
N
Cordes
D000107:Acetylation; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000473:pathology*; D010766:Phosphorylation; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D011838:Radiation-Sensitizing Agents
3D cell culture; Cancer cell lines; DNA repair; HDAC inhibitor; Ionizing radiation