• Clin Cancer Res · Sep 2005

    Activity of suberoylanilide hydroxamic Acid against human breast cancer cells with amplification of her-2.

    • Purva Bali, Michael Pranpat, Ramona Swaby, Warren Fiskus, Hirohito Yamaguchi, Maria Balasis, Kathy Rocha, Hong-Gang Wang, Victoria Richon, and Kapil Bhalla.
    • Department of Interdisciplinary Oncology, Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, Florida 33612, USA.
    • Clin Cancer Res. 2005 Sep 1; 11 (17): 6382-9.

    PurposeWe 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.Experimental DesignThe 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.ResultsTreatment 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.ConclusionsThese preclinical findings support the development of SAHA in combination with docetaxel and/or trastuzumab against Her-2-amplified breast cancer.

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