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B Pathway to Induction of Apoptosis in Human Leukemia Cells by Histone Deacetylase Inhibitors and Flavopiridol
Departments of Medicine (N.G., Y.D., M.R., S.G.), Biochemistry (S.G.), Pharmacology (S.G.), and Radiation Oncology (P.D.), Virginia Commonwealth University/Medical College of Virginia, Richmond, Virginia
Interactions between the cyclin-dependent kinase inhibitor flavopiridol and the histone deacetylase inhibitors (HDACIs) sodium butyrate (NaB) and suberoylanilide hydroxamic acid (SAHA) have been examined in human leukemia cells in relation to effects on nuclear factor 
B (NF-B) activation. Exposure (24 h) of U937 human leukemia cells to NaB (1 mM) or SAHA (1.5 µM) resulted in a marked increase in NF-B DNA binding, effects that were essentially abrogated by coadministration of flavopiridol (100 nM). These events were accompanied by a marked increase in mitochondrial injury, caspase activation, and apoptosis. Mutant cells expressing an IB
super-repressor exhibited impairment of NF-B DNA binding in response to HDACIs and a significant although modest increase in apoptosis. However, disruption of the NF-B pathway also increased mitochondrial injury and caspase activation in response to flavopiridol and to an even greater extent to the combination of flavopiridol and HDACIs. Coadministration of flavopiridol with HDACIs down-regulated the X-linked inhibitor of apoptosis (XIAP), Mcl-1, and p21CIP1/WAF1 and activated c-Jun NH2-terminal kinase; moreover, these effects were considerably more pronounced in IB mutants. Similar responses were observed in U937 mutant cells stably expressing RelA/p65 small interfering RNA. In all cases, flavopiridol was significantly more potent than genetic interruption of the NF-B cascade in promoting HDACI-mediated lethality. Together, these findings are consistent with the notion that although inhibition of NF-B activation by flavopiridol contributes to antileukemic interactions with HDACIs, other NF-B–independent flavopiridol actions (e.g., down-regulation of Mcl-1, XIAP, and p21CIP1/WAF1) play particularly critical roles in this phenomenon.
Address correspondence to: Dr. Steven Grant, Division of Hematology/Oncology, Virginia Commonwealth University/Medical College of Virginia, MCV Station Box 230, Richmond, VA 23298. E-mail: stgrant{at}hsc.vcu.edu
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