Cotreatment with suberanoylanilide hydroxamic acid and 17-allylamino 17-demethoxygeldanamycin synergistically induces apoptosis in Bcr-Abl+ Cells sensitive and resistant to STI571 (imatinib mesylate) in association with down-regulation of Bcr-Abl, abrogation of signal transducer and activator of transcription 5 activity, and Bax conformational change.
Interactions between the histone deacetylase (HDAC) inhibitors suberanoylanilide 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 Bcr-Abl(+) human leukemia cells (K562 and LAMA84), including those sensitive and resistant to STI571 (imatinib mesylate). Cotreatment with 17-AAG and SAHA or SB synergistically induced mitochondrial dysfunction (cytochrome c and apoptosis-inducing factor release), caspase-3 and -8 activation, apoptosis, and growth inhibition. Similar effects were observed in LAMA84 cells and K562 cells resistant to STI571, as well as in CD34(+) cells isolated from the bone marrows of three patients with chronic myelogenous leukemia. These events were associated with increased binding of Bcr-Abl, Raf-1, and Akt to Hsp70, and inactivation of extracellular signal-regulated kinase 1/2 and Akt. In addition, 17-AAG/SAHA abrogated the DNA binding and the transcriptional activities of signal transducer and activator of transcription (STAT) 5 in K562 cells, including those ectopically expressing a constitutively active STAT5A construct. Cotreatment with 17-AAG and SAHA also induced down-regulation of Mcl-1, Bcl-xL, and B-Raf; up-regulation of Bak; cleavage of 14-3-3 proteins; and a profound conformational change in Bax accompanied by translocation to the membrane fraction. Moreover, ectopic expression of Bcl-2 attenuated cell death induced by this regimen, implicating mitochondrial injury in the lethality observed. Together, these findings raise the possibility that combining HDAC inhibitors with the Hsp90 antagonist 17-AAG may represent a novel strategy against Bcr-Abl(+) leukemias, including those resistant to STI571.
Rahmani
Mohamed
M
Division of Hematology/Oncology, Virginia Commonwealth University, Medical College of Virginia, MCV Station Box 230, Richmond, VA 23298, USA.
Reese
Erin
E
Dai
Yun
Y
Bauer
Cheryl
C
Kramer
Lora B
LB
Huang
Mei
M
Jove
Richard
R
Dent
Paul
P
Grant
Steven
S
D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D016227:Benzoquinones; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl / Q000032:analysis*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D000068877:Imatinib Mesylate; D020014:K562 Cells; D047029:Lactams, Macrocyclic; D020930:MAP Kinase Kinase Kinases / Q000502:physiology; D008894:Milk Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry*; D011743:Pyrimidines / Q000494:pharmacology*; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D025521:Tumor Suppressor Proteins; D000077337:Vorinostat; D051028:bcl-2-Associated X Protein; D048490:raf Kinases / Q000502:physiology
C494826:BAX protein, human; D001549:Benzamides; D016227:Benzoquinones; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D047029:Lactams, Macrocyclic; D008894:Milk Proteins; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D017828:Rifabutin; C112765:tanespimycin; D000077337:Vorinostat; D000068877:Imatinib Mesylate; D004247:DNA; D016044:Fusion Proteins, bcr-abl; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048490:raf Kinases; D020930:MAP Kinase Kinase Kinases