Abstract
DNA methylation and BLC-2 are potential therapeutic targets in acute myeloid leukemia (AML). We investigated pharmacologic interaction between the DNA methyltransferase inhibitor 5-azacytidine (5-AZA) and the BCL-2 inhibitor ABT-737. Increased BCL-2 expression determined by reverse phase protein analysis was associated with poor survival in AML patients with unfavorable cytogenetics (n = 195). We found that 5-AZA, which itself has modest apoptotic activity, acts synergistically with ABT-737 to induce apoptosis. The 5-AZA/ABT-737 combination enhanced mitochondrial outer membrane permeabilization, as evidenced by effective conformational activation of BAX and ∆ψ(m) loss. Although absence of p53 limited apoptotic activities of 5-AZA and ABT-737 as single agents, the combination synergistically induced apoptosis independent of p53 expression. 5-AZA down-regulated MCL-1, known to mediate resistance to ABT-737, in a p53-independent manner. The 5-AZA/ABT-737 combination synergistically induced apoptosis in AML cells in seven of eight patients. 5-AZA significantly reduced MCL-1 levels in two of three samples examined. Our data provide a molecular rationale for this combination strategy in AML therapy.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antineoplastic Agents / administration & dosage
-
Antineoplastic Agents / pharmacology*
-
Antineoplastic Agents / therapeutic use
-
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
-
Apoptosis / drug effects*
-
Apoptosis Regulatory Proteins / agonists
-
Apoptosis Regulatory Proteins / antagonists & inhibitors
-
Apoptosis Regulatory Proteins / metabolism
-
Azacitidine / administration & dosage
-
Azacitidine / pharmacology
-
Azacitidine / therapeutic use
-
Biphenyl Compounds / administration & dosage
-
Biphenyl Compounds / pharmacology
-
Biphenyl Compounds / therapeutic use
-
Cell Line, Tumor
-
DNA Modification Methylases / antagonists & inhibitors*
-
Drug Resistance, Neoplasm / drug effects
-
Drug Synergism
-
Enzyme Inhibitors / administration & dosage
-
Enzyme Inhibitors / pharmacology*
-
Enzyme Inhibitors / therapeutic use
-
Humans
-
Leukemia, Myeloid, Acute / drug therapy*
-
Leukemia, Myeloid, Acute / metabolism
-
Leukemia, Myeloid, Acute / pathology
-
Mice
-
Mice, Inbred NOD
-
Mitochondria / drug effects*
-
Neoplasm Proteins / agonists
-
Neoplasm Proteins / antagonists & inhibitors
-
Neoplasm Proteins / genetics
-
Neoplasm Proteins / metabolism
-
Nitrophenols / administration & dosage
-
Nitrophenols / pharmacology
-
Nitrophenols / therapeutic use
-
Piperazines / administration & dosage
-
Piperazines / pharmacology
-
Piperazines / therapeutic use
-
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
-
Sulfonamides / administration & dosage
-
Sulfonamides / pharmacology
-
Sulfonamides / therapeutic use
-
Tumor Cells, Cultured
-
Tumor Suppressor Protein p53 / antagonists & inhibitors
-
Tumor Suppressor Protein p53 / genetics
-
Tumor Suppressor Protein p53 / metabolism
-
Xenograft Model Antitumor Assays
Substances
-
ABT-737
-
Antineoplastic Agents
-
Apoptosis Regulatory Proteins
-
Biphenyl Compounds
-
Enzyme Inhibitors
-
Neoplasm Proteins
-
Nitrophenols
-
Piperazines
-
Proto-Oncogene Proteins c-bcl-2
-
Sulfonamides
-
TP53 protein, human
-
Tumor Suppressor Protein p53
-
DNA Modification Methylases
-
Azacitidine