Combinatorial effects of histone deacetylase inhibitors (HDACi), vorinostat and entinostat, and adaphostin are characterized by distinct redox alterations
Autor: | Tiewei Cheng, Hayley Donnella, Mary E. Irwin, Melissa M. Singh, Nilsa Rivera-Del Valle, Joya Chandra |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Cancer Research Pyridines Adamantane Antineoplastic Agents Apoptosis DNA Fragmentation Toxicology medicine.disease_cause Article Histone Deacetylases 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Line Tumor medicine Humans Pharmacology (medical) Vorinostat Pharmacology biology Entinostat Superoxide Gene Expression Profiling Apoptotic DNA fragmentation Precursor Cell Lymphoblastic Leukemia-Lymphoma Hydroquinones Histone Deacetylase Inhibitors Oxidative Stress 030104 developmental biology Histone Oncology chemistry 030220 oncology & carcinogenesis Benzamides Cancer research biology.protein DNA fragmentation Drug Therapy Combination Histone deacetylase Oxidation-Reduction Oxidative stress medicine.drug |
Popis: | PURPOSE: Amongst the epigenetically-targeted therapies, targeting of the histone deacetylases (HDACs) has yielded numerous drugs for clinical use in hematological malignancies, but none as yet for acute lymphocytic leukemia (ALL). Single agent activity of HDAC inhibitors (HDACi) has been elusive in ALL, and has prompted study of combinatorial strategies. Because several HDACi raise levels of intracellular oxidative stress, we evaluated combinations of two structurally distinct HDACi with the redox active compound adaphostin in acute lymphocytic leukemia (ALL). METHODS: The HDACi vorinostat and entinostat were tested in combination with adaphostin in human ALL cell lines. DNA fragmentation, caspase activation, mitochondrial disruption and levels intracellular peroxides, superoxide and glutathione were measured in cells treated with the HDACi/adaphostin combinations. Antioxidant blockade of cell death induction and gene expression profiling of cells treated with vorinostat/adaphostin versus entinostat/adaphostin combinations was evaluated. RESULTS: Both combinations synergistically induced apoptotic DNA fragmentation, which was preceded by an increase in superoxide levels, a reduction in mitochondrial membrane potential, and an increase in caspase-9 activation. The antioxidant N-acetylcysteine (NAC) blocked superoxide generation and prevented reduction of mitochondrial membrane potential. NAC decreased DNA fragmentation and caspase activity in cells treated with adaphostin and vorinostat, but not in those treated with adaphostin and entinostat. Gene expression arrays revealed differential regulation of several redox genes prior to cell death induction. CONCLUSIONS: A redox modulatory agent, adaphostin, enhances efficacy of two HDACi, vorinostat or entinostat, but via different mechanisms indicating a point of divergence in the mechanisms of synergy between the two distinct HDACi and adaphostin. |
Databáze: | OpenAIRE |
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