title: Vorinostat induces reactive oxygen species and DNA damage in acute myeloid leukemia cells.
abstract: Histone deacetylase inhibitors (HDACi) are promising anti-cancer agents, however, their mechanisms of action remain unclear. In acute myeloid leukemia (AML) cells, HDACi have been reported to arrest growth and induce apoptosis. In this study, we elucidate details of the DNA damage induced by the HDACi vorinostat in AML cells. At clinically relevant concentrations, vorinostat induces double-strand breaks and oxidative DNA damage in AML cell lines. Additionally, AML patient blasts treated with vorinostat display increased DNA damage, followed by an increase in caspase-3/7 activity and a reduction in cell viability. Vorinostat-induced DNA damage is followed by a G2-M arrest and eventually apoptosis. We found that pre-treatment with the antioxidant N-acetyl cysteine (NAC) reduces vorinostat-induced DNA double strand breaks, G2-M arrest and apoptosis. These data implicate DNA damage as an important mechanism in vorinostat-induced growth arrest and apoptosis in both AML cell lines and patient-derived blasts. This supports the continued study and development of vorinostat in AMLs that may be sensitive to DNA-damaging agents and as a combination therapy with ionizing radiation and/or other DNA damaging agents.
authors.affiliation: Lady Davis Institute for Medical Research, Segal Cancer Center, Jewish General Hospital, McGill University, Montreal, Canada.
authors.forename: Luca A
authors.initials: LA
authors.lastname: Petruccelli
authors.forename: Daphné
authors.initials: D
authors.lastname: Dupéré-Richer
authors.forename: Filippa
authors.initials: F
authors.lastname: Pettersson
authors.forename: Hélène
authors.initials: H
authors.lastname: Retrouvey
authors.forename: Sophia
authors.initials: S
authors.lastname: Skoulikas
authors.forename: Wilson H
authors.initials: WH
authors.lastname: Miller
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016195:G2 Phase / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D017382:Reactive Oxygen Species; D000077337:Vorinostat