Interactions between the
histone deacetylase inhibitors (HDACIs)
suberoylanilide hydroxamic acid (SAHA) and
sodium butyrate (SB) and the
heat shock protein (Hsp) 90 antagonist
17-allylamino-17-demethoxygeldanamycin (17-AAG) have been examined in human
leukemia cells (U937). Coadministration of marginally toxic concentrations of
17-AAG with sublethal concentrations of SB or SAHA resulted in highly synergistic induction of mitochondrial damage (i.e.,
cytochrome c release),
caspase-3 and -8 activation, and apoptosis. Similar interactions were noted in human promyelocytic (HL-60) and lymphoblastic (Jurkat)
leukemia cells. These events were accompanied by multiple perturbations in signal transduction, cell cycle, and survival-related pathways, including early down-regulation of Raf-1, inactivation of
extracellular signal-regulated kinase (ERK) 1/2 and
mitogen-activated
protein/ERK
kinase (MEK) 1/2, diminished expression of phospho-Akt, and late activation of c-Jun-NH(2)-terminal
kinase, but no changes in expression of phospho-p38
mitogen-activated protein kinase. Coadministration of
17-AAG blocked SAHA-mediated induction of the
cyclin-dependent kinase inhibitor p21(CIP1) and resulted in reduced expression of p27(KIP1) and p34(cdc2). 17-AAG/SAHA-treated cells also displayed down-regulation of the antiapoptotic
protein Mcl-1 and evidence of Bcl-2 cleavage. Enforced expression of
doxycycline-inducible p21(CIP1) or constitutively active MEK1 significantly diminished 17-AAG/SAHA-mediated lethality, indicating that interference with ERK activation and p21(CIP1) induction play important functional roles in the lethal effects of this regimen. In contrast, enforced expression of constitutively active Akt failed to exert cytoprotective actions. Together, these findings indicate that coadministration of SAHA or SB with the Hsp90 antagonist
17-AAG in human
leukemia cells leads to multiple perturbations in signaling, cell cycle, and survival pathways that culminate in mitochondrial injury and apoptosis. They also raise the possibility that combining such agents with Hsp90 antagonists may represent a novel antileukemic strategy.