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, Kapil Bhalla

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154 Scopus citations

Abstract

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, p27KIP1, 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 p21WAF1 and p27KIP1 levels, increased the percentage of cells in 62-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-xL 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.

Original languageEnglish (US)
Pages (from-to)6382-6389
Number of pages8
JournalClinical Cancer Research
Volume11
Issue number17
DOIs
StatePublished - Sep 1 2005

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Bali, P., Pranpat, M., Swaby, R., Fiskus, W., Yamaguchi, H., Balasis, M., Rocha, K., Wang, H. G., Richon, V., & Bhalla, K. (2005). Activity of suberoylanilide hydroxamic acid against human breast cancer cells with amplification of Her-2. Clinical Cancer Research, 11(17), 6382-6389. https://doi.org/10.1158/1078-0432.CCR-05-0344