TY - JOUR T1 - RETRACTION: Flavopiridol and Histone Deacetylase Inhibitors Promote Mitochondrial Injury and Cell Death in Human Leukemia Cells That Overexpress Bcl-2 JF - Molecular Pharmacology JO - Mol Pharmacol SP - 288 LP - 298 DO - 10.1124/mol.105.016154 VL - 69 IS - 1 AU - Girija Dasmahapatra AU - Jorge A. Almenara AU - Steven Grant Y1 - 2006/01/01 UR - http://molpharm.aspetjournals.org/content/69/1/288.abstract N2 - Interactions between the cyclin-dependent kinase (CDK) inhibitor flavopiridol and histone deacetylase (HDAC) inhibitors (suberoylanilide hydroxamide and sodium butyrate) were examined in human leukemia cells (U937 and HL-60) ectopically expressing Bcl-2/Bcl-xL and in primary AML cells. Coadministration of flavopiridol with HDAC inhibitors synergistically potentiated mitochondrial damage (cytochrome c, second mitochondria-derived activator of caspases/direct IAP binding protein with low pI, and apoptosis-inducing factor release), caspase activation, poly(ADP-ribose) polymerase degradation, and cell death in both wild type and Bcl-2- or Bcl-xL-overexpressing cells and induced a pronounced loss of clonogenicity. In contrast, Bcl-2 and Bcl-xL largely blocked these events in cells exposed to the cytotoxic agent 1-β-d-arabinofuranosylcytosine (ara-C). Enforced expression of dominant-negative Fas-associated death domain failed to protect cells from the flavopiridol/histone deacetylase inhibitor (HDACI) regimen, arguing against the involvement of the receptor pathway in lethality. Ectopic expression of a phosphorylation loop-deleted Bcl-2 or Bcl-2 lacking the serine70 phosphorylation site, which dramatically protected cells from ara-C lethality, delayed but did not prevent flavopiridol/HDAC inhibitor-induced mitochondrial injury, cell death, or loss of clonogenicity. Ectopic expression of Bcl-2 or Bcl-xL was also unable to prevent the flavopiridol/HDACI regimen from inducing a conformational change in and mitochondrial translocation of Bax, and it did not attenuate Bax dimerization. As a whole, these findings indicate that in contrast to certain conventional cytotoxic agents such as ara-C, overexpression of Bcl-2 or Bcl-xL are largely ineffective in preventing perturbations in Bax, mitochondrial injury, and cell death in human leukemia cells subjected to simultaneous CDK and HDAC inhibition. They also raise the possibility that a strategy combining CDK and HDAC inhibitors may be effective against drug-resistant leukemia cells overexpressing Bcl-2 or Bcl-xL. ER -