Skip directly to search Skip directly to A to Z list Skip directly to page options Skip directly to site content

NIOSHTIC-2 Publications Search

Search Results

Synergistic antileukemic interactions between 2-medroxyestradiol (2-ME) and histone deacetylase inhibitors involve Akt down-regulation and oxidative stress.

Authors
Gao-N; Rahmani-M; Shi-XL; Dent-P; Grant-S
Source
Blood 2006 Jan; 107(1):241-249
NIOSHTIC No.
20029266
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.
Keywords
Cell-cultures; Bone-marrow; Free-radicals; Synergism; Cell-biology; Cell-function; Blood-cells
CODEN
BLOOAW
Publication Date
20060101
Document Type
Journal Article
Fiscal Year
2006
NTIS Accession No.
NTIS Price
Issue of Publication
1
ISSN
0006-4971
NIOSH Division
HELD
Priority Area
Research Tools and Approaches: Cancer Research Methods
Source Name
Blood
State
WV; VA
TOP