Activity of suberoylanilide hydroxamic Acid against human breast cancer cells with amplification of her-2.
We determined the effects of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on hsp90 and its client proteins Her-2, AKT, and c-Raf, as well as evaluated the cytotoxic effects of co-treatment of SAHA with trastuzumab or docetaxel in human breast cancer BT-474 and SKBR-3 cells containing amplification of Her-2.The ... cells were treated with SAHA (1.0-5.0 micromol/L) and/or trastuzumab (5-40 microg/mL) or docetaxel (5-20 nmol/L). Following this, apoptosis and the levels of p21(WAF1), p27(KIP1), AKT, c-Raf, and Her-2, as well as of the key regulators of apoptosis were determined. Synergistic interaction between drugs was evaluated by median dose-effect analysis.Treatment with SAHA up-regulated p21(WAF1) and p27(KIP1) levels, increased the percentage of cells in G2-M phase of the cell cycle, as well as induced apoptosis in a dose-dependent manner. This was associated with up-regulation of the pro-death Bak and Bim, as well as with attenuation of the levels of Her-2 and XIAP, survivin, Bcl-2, and Bcl-x(L) proteins. SAHA treatment induced acetylation of hsp90. This reduced the chaperone association of Her-2 with hsp90, promoting polyubiquitylation and degradation of Her-2. SAHA also attenuated the levels of c-Raf and AKT. Co-treatment with SAHA significantly increased trastuzumab or docetaxel-induced apoptosis of BT-474 and SKBR-3 cells. Additionally, median dose-effect analysis revealed that co-treatment with SAHA and trastuzumab or docetaxel induced synergistic cytotoxic effects against the breast cancer cells.These preclinical findings support the development of SAHA in combination with docetaxel and/or trastuzumab against Her-2-amplified breast cancer.
Mesh Terms:
Acetylation, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Blotting, Western, Breast Neoplasms, Cell Cycle Proteins, Cell Division, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Drug Synergism, Flow Cytometry, G2 Phase, Gene Amplification, HSP90 Heat-Shock Proteins, Histone Deacetylase Inhibitors, Humans, Hydroxamic Acids, Inhibitor of Apoptosis Proteins, Microtubule-Associated Proteins, Neoplasm Proteins, Proteasome Endopeptidase Complex, Protein-Serine-Threonine Kinases, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-bcl-2, Proto-Oncogene Proteins c-raf, Receptor, ErbB-2, Signal Transduction, Taxoids, Trastuzumab, Tumor Cells, Cultured, Tumor Suppressor Proteins, X-Linked Inhibitor of Apoptosis Protein, bcl-X Protein
Acetylation, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Blotting, Western, Breast Neoplasms, Cell Cycle Proteins, Cell Division, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Drug Synergism, Flow Cytometry, G2 Phase, Gene Amplification, HSP90 Heat-Shock Proteins, Histone Deacetylase Inhibitors, Humans, Hydroxamic Acids, Inhibitor of Apoptosis Proteins, Microtubule-Associated Proteins, Neoplasm Proteins, Proteasome Endopeptidase Complex, Protein-Serine-Threonine Kinases, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-bcl-2, Proto-Oncogene Proteins c-raf, Receptor, ErbB-2, Signal Transduction, Taxoids, Trastuzumab, Tumor Cells, Cultured, Tumor Suppressor Proteins, X-Linked Inhibitor of Apoptosis Protein, bcl-X Protein
Clin. Cancer Res.
Date: Sep. 01, 2005
PubMed ID: 16144943
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