Activity of suberoylanilide hydroxamic acid against human breast cancer cells with amplification of Her-2
Activity of suberoylanilide hydroxamic acid against human breast cancer cells with amplification of Her-2
复制标题
DOI：
10.1158/1078-0432.ccr-05-0344
复制
发表时间：
2005-09-01
影响因子：
11.5
通讯作者：
Bhalla, K
中科院分区：
文献类型：
--
作者：
Bali, P;Pranpat, M;Bhalla, K
目的：我们确定了辛二酰苯胺异羟肟酸（SAHA）（一种组蛋白去乙酰化酶抑制剂）对hsp 90及其客户蛋白Her-2、AKT和c-Raf的作用，并评估了SAHA与曲妥珠单抗或多西他赛在含有Her-2扩增的人乳腺癌BT-474和SKBR-3细胞中的细胞毒性作用。用SAHA（1.0-5.0 μ mol/L）和/或曲妥珠单抗（5-40 μ g/mL）或多西他赛（5-20 nmol/L）处理细胞。在此之后，确定细胞凋亡和p21（WAF 1）、P27（KIP 1）、AKT、c-Raf和Her-2以及细胞凋亡的关键调节因子的水平。结果：SAHA可上调p21（WAF 1）和p27（KIP 1）表达，增加G2-M期细胞比例，并呈剂量依赖性诱导细胞凋亡。这与促死亡巴克和Bim的上调以及Her-2和XIAP、存活素、Bcl-2和BCl-x（L）蛋白水平的减弱有关。SAHA处理诱导hsp 90的乙酰化。这减少了Her-2与hsp 90的伴侣缔合，促进了Her-2的多聚泛素化和降解。SAHA还可降低c-Raf和AKT的水平，SAHA可显著增加曲妥珠单抗或紫杉醇诱导的BT-474和SKBR-3细胞凋亡。此外，中位剂量效应分析显示，与SAHA和曲妥珠单抗或多西他赛诱导协同细胞毒作用对乳腺癌cells.Conclusions：这些临床前研究结果支持SAHA与多西他赛和/或曲妥珠单抗联合对Her-2扩增的乳腺癌的发展。
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 mu mol/L) and/or trastuzumab (5-40 mu g/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 G(2)-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.