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

@article{citeulike:495632, 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 {micro}mol/L) and/or trastuzumab (5-40 {micro}g/mL) or docetaxel (5-20 nmol/L). Following this, apoptosis and the levels of p21WAF1, 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 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-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.}, author = {Bali, Purva and Pranpat, Michael and Swaby, Ramona and Fiskus, Warren and Yamaguchi, Hirohito and Balasis, Maria and Rocha, Kathy and Wang, Hong-Gang and Richon, Victoria and Bhalla, Kapil}, citeulike-article-id = {495632}, citeulike-linkout-0 = {http://clincancerres.aacrjournals.org/cgi/content/abstract/11/17/6382}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/16144943}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=16144943}, day = {1}, journal = {Clin Cancer Res}, keywords = {akt, hdac, her2}, month = {September}, number = {17}, pages = {6382--6389}, posted-at = {2006-02-07 13:57:16}, priority = {2}, title = {Activity of Suberoylanilide Hydroxamic Acid Against Human Breast Cancer Cells with Amplification of Her-2}, url = {http://clincancerres.aacrjournals.org/cgi/content/abstract/11/17/6382}, volume = {11}, year = {2005} }

TY - JOUR ID - citeulike:495632 L3 - citeulike-article-id:495632 N2 - 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 {micro}mol/L) and/or trastuzumab (5-40 {micro}g/mL) or docetaxel (5-20 nmol/L). Following this, apoptosis and the levels of p21WAF1, 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 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-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. IS - 17 JF - Clin Cancer Res EP - 6389 TI - Activity of Suberoylanilide Hydroxamic Acid Against Human Breast Cancer Cells with Amplification of Her-2 VL - 11 SP - 6382 KW - akt KW - hdac KW - her2 AU - Bali, Purva AU - Pranpat, Michael AU - Swaby, Ramona AU - Fiskus, Warren AU - Yamaguchi, Hirohito AU - Balasis, Maria AU - Rocha, Kathy AU - Wang, Hong-Gang AU - Richon, Victoria AU - Bhalla, Kapil PY - 2005/09/01/ UR - http://clincancerres.aacrjournals.org/cgi/content/abstract/11/17/6382 ER -