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

Ramadevi Nimmanapalli; Lianne Fuino; Purva Bali; Maura Gasparetto; Michele Glozak; Jianguo Tao; Lynn Moscinski; Clayton Smith; Jie Wu; Richard Jove; Peter Atadja; Kapil Bhalla

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

Cancer Res. 2003 Aug 15;63(16):5126-35.

Authors

Ramadevi Nimmanapalli¹, Lianne Fuino, Purva Bali, Maura Gasparetto, Michele Glozak, Jianguo Tao, Lynn Moscinski, Clayton Smith, Jie Wu, Richard Jove, Peter Atadja, Kapil Bhalla

Affiliation

¹ Department of Interdisciplinary Oncology, Moffitt Cancer Center and Research Institute University of South Florida, Tampa, Florida 33614, USA.

PMID: 12941844

Abstract

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.

MeSH terms

Acetylation
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Benzamides
Blast Crisis / drug therapy*
Cyclin-Dependent Kinase Inhibitor p21
Cyclins / biosynthesis
Cysteine Endopeptidases / physiology*
Drug Resistance, Neoplasm
Enzyme Inhibitors / pharmacology*
Fusion Proteins, bcr-abl / genetics
Fusion Proteins, bcr-abl / metabolism*
G1 Phase / drug effects
Histone Deacetylase Inhibitors*
Humans
Hydroxamic Acids / pharmacology*
Imatinib Mesylate
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
Microfilament Proteins / biosynthesis
Multienzyme Complexes / physiology*
Muscle Proteins*
Piperazines / pharmacology*
Promoter Regions, Genetic
Proteasome Endopeptidase Complex
Pyridones / pharmacology
Pyrimidines / pharmacology*
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Benzamides
CDKN1A protein, human
Cyclin-Dependent Kinase Inhibitor p21
Cyclins
Enzyme Inhibitors
Histone Deacetylase Inhibitors
Hydroxamic Acids
LAQ824
Microfilament Proteins
Multienzyme Complexes
Muscle Proteins
Piperazines
Pyridones
Pyrimidines
Tagln protein, mouse
Imatinib Mesylate
Fusion Proteins, bcr-abl
Cysteine Endopeptidases
Proteasome Endopeptidase Complex
PD 180970