Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B.
Histone deacetylase inhibitors induce hyperacetylation of the amino-terminal lysine residues of the core nucleosomal histones, which results in chromatin remodeling and altered gene expression. Present studies demonstrate that exposure to a novel hydroxamic acid analogue histone deacetylase inhibitor, LAQ824, induced p21WAF1 and p27KIP1 and caused growth arrest and apoptosis of human breast cancer SKBR-3 and BT-474 cells that possess amplification and overexpression of Her-2/neu. Treatment with LAQ824 depleted the mRNA and protein levels of Her-2/neu-encoded Her-2, which was associated with attenuation of pAKT, c-Raf-1, and phosphorylated mitogen-activated protein kinase levels. LAQ824 also induced the acetylation of heat shock protein (hsp) 90, resulting in inhibition of its binding to ATP, which has been shown to impair the chaperone association of hsp 90 with its client proteins, Her-2, AKT, and c-Raf-1. Consistent with this, treatment with LAQ824 shifted the binding of Her-2 from hsp 90 to hsp 70, promoting proteasomal degradation of Her-2. Thus, LAQ824 depletes Her-2 through two mechanisms: attenuation of its mRNA levels and promotion of its degradation by the proteasome. Following LAQ824 treatment, the cell membrane association, autotyrosine phosphorylation, and colocalization of Her-2 with HER-3 also declined. Cotreatment with LAQ824 significantly increased trastuzumab-induced apoptosis of BT-474 and SKBR-3 cells. This was associated with greater attenuation of Her-2, c-Raf-1, and pAKT levels. LAQ824 also enhanced taxotere-induced, epothilone B-induced, and gemcitabine-induced apoptosis of BT-474 and SKBR-3 cells. These findings suggest that LAQ824 is active against human breast cancer cells and has the potential to improve the efficacy of trastuzumab, taxotere, gemcitabine, and epothilone B against breast cancer with Her-2/neuamplification.
Department of Interdisciplinary Oncology, Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL 33612, USA.
Lianne
L
Fuino
Purva
P
Bali
Sylvie
S
Wittmann
Sreenivas
S
Donapaty
Fei
F
Guo
Hirohito
H
Yamaguchi
Hong-Gang
HG
Wang
Peter
P
Atadja
Kapil
K
Bhalla
D017304:Annexin A5 / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D004396:Coloring Agents / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003902:Detergents / Q000494:pharmacology; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D034261:Epothilones / Q000494:pharmacology*; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D009097:Multienzyme Complexes / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D046988:Proteasome Endopeptidase Complex; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012685:Sepharose / Q000494:pharmacology; D043823:Taxoids / Q000494:pharmacology*; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D000068878:Trastuzumab; D000093542:Gemcitabine
D017304:Annexin A5; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D002843:Chromatin; D004396:Coloring Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D003546:Cysteine Endopeptidases; D003841:Deoxycytidine; D003902:Detergents; D000077143:Docetaxel; D004791:Enzyme Inhibitors; D034261:Epothilones; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009097:Multienzyme Complexes; D046988:Proteasome Endopeptidase Complex; D018719:Erb-b2 Receptor Tyrosine Kinases; D012685:Sepharose; D043823:Taxoids; D013778:Tetrazolium Salts; D013844:Thiazoles; D000068878:Trastuzumab; D000093542:Gemcitabine; C493956:CDKN1A protein, human; C477361:LAQ824; C022616:thiazolyl blue; C093788:epothilone B