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.