title: Antioxidants impair anti-tumoral effects of Vorinostat, but not anti-neoplastic effects of Vorinostat and caspase-8 downregulation.
abstract: We have recently demonstrated that histone deacetylase inhibitor, Vorinostat, applied as a single therapy or in combination with caspase-8 downregulation exhibits high anti-tumoral activity on endometrial carcinoma cell lines. In the present study, we have assessed the signalling processes underlying anti-tumoral effects of Vorinostat. Increasing evidence suggests that reactive oxygen species are responsible for histone deacetylase inhibitor-induced cell killing. We have found that Vorinostat induces formation of reactive oxygen species and DNA damage. To investigate the role of oxidative stress as anti-neoplastic mechanism, we have evaluated the effects of different antioxidants (Bha, Nac and Tiron) on endometrial carcinoma cell line Ishikawa treated with Vorinostat. We show that Bha, Nac and Tiron markedly inhibited the cytotoxic effects of Vorinostat, increasing cell viability in vitro. We found that all three antioxidants did not inhibited accumulation of acetyl Histone H4, so that antioxidants did not inhibit Vorinostat activity. Finally, we have evaluated the effects of antioxidants on anti-tumoral activity of Vorinostat as monotherapy or in combination with caspase-8 downregulation in vivo. Interestingly, antioxidants blocked the reduction of tumour growth caused by Vorinostat, but they were unable to inhibit anti-tumoral activity of Vorinostat plus caspase-8 inhibition.
authors.affiliation: Oncologic Pathology Group, Department de Ciències Mèdiques Bàsiques, Universitat de Lleida, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomèdica de Lleida, IRBLleida, Lleida, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Bergadà
authors.affiliation: Oncologic Pathology Group, Department de Ciències Mèdiques Bàsiques, Universitat de Lleida, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomèdica de Lleida, IRBLleida, Lleida, Spain.
authors.forename: Andree
authors.initials: A
authors.lastname: Yeramian
authors.affiliation: Oncologic Pathology Group, Department de Ciències Mèdiques Bàsiques, Universitat de Lleida, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomèdica de Lleida, IRBLleida, Lleida, Spain.
authors.forename: Annabel
authors.initials: A
authors.lastname: Sorolla
authors.affiliation: Oncologic Pathology Group, Department de Ciències Mèdiques Bàsiques, Universitat de Lleida, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomèdica de Lleida, IRBLleida, Lleida, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Matias-Guiu
authors.affiliation: Oncologic Pathology Group, Department de Ciències Mèdiques Bàsiques, Universitat de Lleida, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomèdica de Lleida, IRBLleida, Lleida, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Dolcet
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053181:Caspase 8 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004336:Drug Antagonism; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D014410:Tumor Stem Cell Assay; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D017382:Reactive Oxygen Species; D000077337:Vorinostat; D053181:Caspase 8