title: The antihypertensive drug hydralazine activates the intrinsic pathway of apoptosis and causes DNA damage in leukemic T cells.
abstract: Epigenetic therapies have emerged as promising anticancer approaches, since epigenetic modifications play a major role in tumor initiation and progression. Hydralazine, an approved vasodilator and antihypertensive drug, has been recently shown to act as a DNA methylation inhibitor. Even though hydralazine is already tested in clinical cancer trials, its mechanism of antitumor action remains undefined. Here, we show that hydralazine induced caspase-dependent apoptotic cell death in human p53-mutant leukemic T cells. Moreover, we demonstrate that hydralazine triggered the mitochondrial pathway of apoptosis by inducing Bak activation and loss of the mitochondrial membrane potential. Hydralazine treatment further resulted in the accumulation of reactive oxygen species, whereas a superoxide dismutase mimetic inhibited hydralazine-induced cell death. Interestingly, caspase-9-deficient Jurkat cells or Bcl-2- and Bcl-xL-overexpressing cells were strongly resistant to hydralazine treatment, thereby demonstrating the dependence of hydralazine-induced apoptosis on the mitochondrial death pathway. Furthermore, we demonstrate that hydralazine treatment triggered DNA damage which might contribute to its antitumor effect.
authors.affiliation: Unidad de Inmunología, IBIMER, Universidad de Granada, Granada, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Ruiz-Magaña
authors.affiliation: Unidad de Inmunología, IBIMER, Universidad de Granada, Granada, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Martínez-Aguilar
authors.affiliation: Unidad de Inmunología, IBIMER, Universidad de Granada, Granada, Spain.
authors.forename: Estefanía
authors.initials: E
authors.lastname: Lucendo
authors.affiliation: Unidad de Inmunología, IBIMER, Universidad de Granada, Granada, Spain.
authors.forename: Diana
authors.initials: D
authors.lastname: Campillo-Davo
authors.affiliation: Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.|German Cancer Consortium (DKTK) and German Research Cancer Center (DKFZ), Heidelberg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulze-Osthoff
authors.affiliation: Unidad de Inmunología, IBIMER, Universidad de Granada, Granada, Spain.|Departamento de Bioquímica y Biología Molecular 3 e Inmunología, Facultad de Medicina, Universidad de Granada, Granada, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ruiz-Ruiz
mesh_terms: D000959:Antihypertensive Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects*; D006801:Humans; D006830:Hydralazine / Q000494:pharmacology*; D019169:Jurkat Cells; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
chemical_list: D000959:Antihypertensive Agents; D000970:Antineoplastic Agents; D006830:Hydralazine
keywords: DNA damage; apoptosis; hydralazine; leukemia; mitochondria