title: Synergistic antileukemic interactions between 2-medroxyestradiol (2-ME) and histone deacetylase inhibitors involve Akt down-regulation and oxidative stress.
abstract: Interactions between the endogenous estradiol metabolite 2-medroxyestradiol (2-ME) and histone deacetylase inhibitors (HDACIs) have been investigated in human leukemia cells. Coadministration of subtoxic or marginally toxic concentrations of 2-ME and SAHA or sodium butyrate in diverse human leukemia-cell types resulted in a marked increase in oxidative damage (eg, generation of reactive oxygen species [ROSs]), mitochondrial injury (eg, cytochrome c release and Bax translocation), caspase activation, and apoptosis. These interactions were also noted in primary human leukemia cells but not in normal bone marrow CD34+ cells. Synergistic interactions between these agents were associated with inactivation of Akt and activation of c-Jun N-terminal kinase (JNK). Essentially all of these events were reversed by free radical scavengers such as the manganese superoxide dismutase (MnSOD) mimetic TBAP and catalase. Notably, treatment with 2-ME/HDACIs resulted in down-regulation of thioredoxin, MnSOD, and glutathione peroxidase. Enforced activation of Akt blocked 2-ME/HDACI-mediated mitochondrial injury, caspase activation, and JNK up-regulation, but not generation of ROSs. Pharmacologic or genetic (siRNA) interruption of the JNK pathway also significantly attenuated the lethality of this regimen. Together, these findings support a model in which antileukemic synergism between 2-ME and HDACIs stems primarily from induction of oxidative damage, leading in turn to Akt inactivation and JNK activation, culminating in mitochondrial injury and apoptosis. They also raise the possibility that these events may preferentially occur in leukemic versus normal hematopoietic cells.
authors.affiliation: Department of Medicine, Virginia Commonwealth University/Medical College of Virginia, Richmond, VA, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Gao
authors.forename: Mohamed
authors.initials: M
authors.lastname: Rahmani
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects; D007938:Leukemia / Q000188:drug therapy / Q000473:pathology; D008928:Mitochondria / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*
chemical_list: D016166:Free Radical Scavengers; D056572:Histone Deacetylase Inhibitors; D004958:Estradiol; C037235:4-hydroxy-2-methylestradiol; D051058:Oncogene Protein v-akt; D048031:JNK Mitogen-Activated Protein Kinases