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Activity of Suberoylanilide Hydroxamic Acid Against Human Breast Cancer Cells with Amplification of Her-2

Authors' Affiliations: ¹ Department of Interdisciplinary Oncology, Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, Florida; ² Fox Chase Cancer Center, Philadelphia, Pennsylvania; and ³ Merck & Co., Inc., Boston, Massachusetts

Requests for reprints: Kapil Bhalla, Department of Interdisciplinary Oncology, Moffitt Cancer Center and Research Institute, University of South Florida, 12902 Magnolia Drive, MRC 3 East, Room 3056, Tampa, FL 33612. Phone: 813-903-6861; Fax: 813-903-6817; E-mail: bhallakn{at}moffitt.usf.edu.

Purpose: 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 cotreatment of SAHA with trastuzumab or docetaxel in human breast cancer BT-474 and SKBR-3 cells containing amplification of Her-2.

Experimental Design: The cells were treated with SAHA (1.0-5.0 µmol/L) and/or trastuzumab (5-40 µg/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.

Results: 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. Cotreatment with SAHA significantly increased trastuzumab or docetaxel-induced apoptosis of BT-474 and SKBR-3 cells. Additionally, median dose-effect analysis revealed that cotreatment with SAHA and trastuzumab or docetaxel induced synergistic cytotoxic effects against the breast cancer cells.

Conclusions: These preclinical findings support the development of SAHA in combination with docetaxel and/or trastuzumab against Her-2-amplified breast cancer.

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