Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3.
Present studies show that LBH589, a novel cinnamic hydroxamic acid analog histone deacetylase inhibitor, induces acetylation of histone H3 and H4 and of heat shock protein 90 (hsp90), increases p21 levels, as well as induces cell-cycle G(1) phase accumulation and apoptosis of the human chronic myeloid leukemia blast crisis (CML-BC) K562 cells and acute leukemia MV4-11 cells with the activating length mutation of FLT-3. In MV4-11 cells, this was associated with marked attenuation of the protein levels of p-FLT-3, FLT-3, p-AKT, and p-ERK1/2. In K562 cells, exposure to LBH589 attenuated Bcr-Abl, p-AKT, and p-ERK1/2. Treatment with LBH589 inhibited the DNA binding activity of signal transducers and activators of transcription 5 (STAT5) in both K562 and MV4-11 cells. The hsp90 inhibitor 17-allyl-amino-demethoxy geldanamycin (17-AAG) also induced polyubiquitylation and proteasomal degradation of FLT-3 and Bcr-Abl by reducing their chaperone association with hsp90. Cotreatment with LBH589 and 17-AAG exerted synergistic apoptosis of MV4-11 and K562 cells. In the imatinib mesylate (IM)-refractory leukemia cells expressing Bcr-Abl with the T315I mutation, treatment with the combination attenuated the levels of the mutant Bcr-Abl and induced apoptosis. Finally, cotreatment with LBH589 and 17-AAG also induced more apoptosis of IM-resistant primary CML-BC and acute myeloid leukemia (AML) cells (with activating mutation of FLT-3) than treatment with either agent alone.
George
Prince
P
Department of Interdisciplinary Oncology Program, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
Bali
Purva
P
Annavarapu
Srinivas
S
Scuto
Anna
A
Fiskus
Warren
W
Guo
Fei
F
Sigua
Celia
C
Sondarva
Gautam
G
Moscinski
Lynn
L
Atadja
Peter
P
Bhalla
Kapil
K
D000208:Acute Disease; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D016227:Benzoquinones; D001752:Blast Crisis / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004338:Drug Combinations; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000068877:Imatinib Mesylate; D007211:Indoles; D020014:K562 Cells; D047029:Lactams, Macrocyclic; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000077767:Panobinostat; D010879:Piperazines / Q000494:pharmacology; D017354:Point Mutation; D025821:Polyubiquitin / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051941:fms-Like Tyrosine Kinase 3
D001549:Benzamides; D016227:Benzoquinones; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D047029:Lactams, Macrocyclic; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D025821:Polyubiquitin; D017828:Rifabutin; C112765:tanespimycin; D000068877:Imatinib Mesylate; D000077767:Panobinostat; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D016044:Fusion Proteins, bcr-abl; D046988:Proteasome Endopeptidase Complex