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Blood, 1 January 2006, Vol. 107, No. 1, pp. 241-249. Prepublished online as a Blood First Edition Paper on September 1, 2005; DOI 10.1182/blood-2005-06-2409. This Article Full Text (PDF) All Versions of this Article: 2005-06-2409v1 107/1/241    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gao, N. Articles by Grant, S. Search for Related Content PubMed PubMed Citation Articles by Gao, N. Articles by Grant, S. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 16, 2005 Accepted August 22, 2005 Synergistic antileukemic interactions between 2-medroxyestradiol (2-ME) and histone deacetylase inhibitors involves Akt down-regulation and oxidative stress Ning Gao, Mohamed Rahmani, Xianglin Shi, Paul Dent, and Steven Grant* Departments of Medicine, Virginia Commonwealth University/Medical College of Virginia, Richmond, VA, USA Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, USA Departments of Medicine, Virginia Commonwealth University/Medical College of Virginia, Richmond, VA, USA; Pharmacology, Virginia Commonwealth University/Medical College of Virginia, Richmond, VA, USA; Radiation Oncology, Virginia Commonwealth University/Medical College of Virginia, Richmond, VA, USA Departments of Medicine, Virginia Commonwealth University/Medical College of Virginia, Richmond, VA, USA; Biochemistry, Virginia Commonwealth University/Medical College of Virginia, Richmond, VA, USA; Pharmacology, Virginia Commonwealth University/Medical College of Virginia, Richmond, VA, USA * Corresponding author; email: stgrant{at}hsc.vcu.edu. Interactions between the endogenous estradiol metabolite 2-ME and histone deacetylase inhibitors (HDACIs) have been investigated in human leukemia cells. Co-administration of sub- 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 (e.g., generation of reactive oxygen species; ROS), mitochondrial injury (e.g., cytochrome c relase 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 JNK(c-Jun N-terminal kinase). Essentially all of these events were reversed by free radical scavengers such as the MnSOD mimetic TBAP, catalase, and ectopic expression of glutathione peroxidase(GPx). Notably, 2-ME/HDACIs treatment resulted in down-regulation of thioredoxin (Trx), MnSOD, and glutathione peroxidase. Enforced activation of Akt blocked 2-ME/HDACIs-mediated mitochondrial injury, caspase activation, and JNK up-regulation, but not ROS generation. 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: ROS `n' roll: a bunch of JNK? Steven D. Gore Blood 2006 107: 9-10. 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