Histone deacetylase inhibitor LAQ824 both lowers expression and promotes proteasomal degradation of Bcr-Abl and induces apoptosis of imatinib mesylate-sensitive or -refractory chronic myelogenous leukemia-blast crisis cells.
Treatment with LAQ824 (Novartis Pharmaceutical, Inc.), a cinnamyl hydroxamic acid analogue inhibitor of histone deacetylases, depleted the mRNA and protein expression of Bcr-Abl in human chronic myeloid leukemia blast crisis (CML-BC) cells. Exposure to LAQ824 induced the expression of the cell cycle-dependent kinase inhibitors p21 and p27 and caused cell cycle G(1)-phase accumulation and apoptosis of CML-BC cells. LAQ824 also induced acetylation of heat shock protein 90. This inhibited the chaperone association of Bcr-Abl with heat shock protein 90, thereby promoting the proteasomal degradation of Bcr-Abl. Cotreatment with LAQ824 increased imatinib mesylate-induced apoptosis of CML-BC cells. Additionally, LAQ824 down-regulated the levels of mutant Bcr-Abl possessing the T315I point mutation, as well as induced apoptosis of imatinib-refractory primary CML-BC cells. Therefore, LAQ824 may be a promising therapeutic agent in the treatment of imatinib-sensitive or -refractory human leukemia.
Nimmanapalli
Ramadevi
R
Department of Interdisciplinary Oncology, Moffitt Cancer Center and Research Institute University of South Florida, Tampa, Florida 33614, USA.
Fuino
Lianne
L
Bali
Purva
P
Gasparetto
Maura
M
Glozak
Michele
M
Tao
Jianguo
J
Moscinski
Lynn
L
Smith
Clayton
C
Wu
Jie
J
Jove
Richard
R
Atadja
Peter
P
Bhalla
Kapil
K
D000107:Acetylation; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D001752:Blast Crisis / Q000188:drug therapy*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D003546:Cysteine Endopeptidases / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D016193:G1 Phase / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008840:Microfilament Proteins / Q000096:biosynthesis; D009097:Multienzyme Complexes / Q000502:physiology*; D009124:Muscle Proteins; D010879:Piperazines / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex; D011728:Pyridones / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001549:Benzamides; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C477361:LAQ824; D008840:Microfilament Proteins; D009097:Multienzyme Complexes; D009124:Muscle Proteins; D010879:Piperazines; D011728:Pyridones; D011743:Pyrimidines; C058992:Tagln protein, mouse; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C410732:PD 180970