Potentiation of paclitaxel activity by the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin in human ovarian carcinoma cell lines with high levels of activated AKT (Retracted article. See vol. 17, pg. 2075, 2018)
Potentiation of paclitaxel activity by the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin in human ovarian carcinoma cell lines with high levels of activated AKT (Retracted article. See vol. 17, pg. 2075, 2018)
复制标题
DOI：
10.1158/1535-7163.mct-05-0445
复制
发表时间：
2006-05-01
影响因子：
5.7
通讯作者：
Jackman, Ann L.
中科院分区：
文献类型：
--
作者：
Sain, Nivedita;Krishnan, Bhavani;Jackman, Ann L.
磷脂酰肌醇-3-激酶(PI3K)/AKT存活通路的激活是卵巢癌细胞毒性耐药的机制之一，该通路的抑制剂可对细胞毒性药物增敏。HSP90抑制剂17-烯丙基氨基-17-去甲氧基格尔达霉素（17-AAG）会消耗一些参与PI3K/AKT信号传导的蛋白，如ERBB2、表皮生长因子受体（EGFR）和磷酸化AKT （p-AKT）。将17-AAG和紫杉醇以其IC50的固定1:1比例联合应用于4种不同表达p-AKT、EGFR和ERBB2的卵巢癌细胞系。egfr过表达的A431和KB表皮样细胞系也包括在内。使用中效方程计算组合指数（CO），并在17- aag介导的PI3K信号抑制的背景下进行解释。在IGROV-1-和erbb2过表达的SKOV-3卵巢癌细胞中观察到协同作用，这些细胞表达高水平的组成性活化的p-AKT [Cl在未受影响的部分（fu）（0.5）分别= 0.50和0.53]。在A431细胞中观察到轻微的协同作用（中度p-AKT/过表达的EGFR， CI在fu(0.5) = 0.76），而在CH1细胞（中度p-AKT）、HX62细胞（低p-AKT）和KB细胞（低p-AKT/过表达的EGFR， CI在fu（50）分别= 3.0、3.5和2.0）中观察到拮抗作用。观察到的效应与细胞凋亡诱导率的变化有关。17-AAG在IC50浓度下诱导SKOV-3、IGROV-1和CH1细胞中HSP90客户蛋白（如C-RAF、ERBB2和p-AKT）或下游活性标记物（如磷酸化的细胞外信号调节激酶或p-AKT）的降低。非生长抑制浓度（6 nmol/L）降低AKT（但不影响细胞外信号调节激酶）的磷酸化，并使SKOV-3细胞对紫杉醇敏感。总之，17-AAG可能使卵巢癌的一个亚群对紫杉醇敏感，特别是那些由ERBB2和/或p-AKT驱动耐药的肿瘤。
Activation of the phosphatidylinositol-3-kinase (PI3K)/AKT survival pathway is a mechanism of cytotoxic drug resistance in ovarian cancer, and inhibitors of this pathway can sensitize to cytotoxic drugs. The HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) depletes some proteins involved in PI3K/AKT signaling, e.g., ERBB2, epidermal growth factor receptor (EGFR), and phosphorylated AKT (p-AKT). 17-AAG and paclitaxel were combined (at a fixed 1:1 ratio of their IC50) in four ovarian cancer cell lines that differ in expression of p-AKT, EGFR, and ERBB2. The EGFR-overexpressing A431 and KB epidermoid cell lines were also included. Combination indices (CO were calculated using the median-effect equation and interpreted in the context of 17-AAG-mediated inhibition of PI3K signaling. Synergy was observed in IGROV-1- and ERbB2-overexpressing SKOV-3 ovarian cancer cells that express a high level of constitutively activated p-AKT [Cl at fraction unaffected (fu)(0.5) = 0.50 and 0.53, respectively]. Slight synergy was observed in A431 cells (moderate p-AKT/overexpressed EGFR; CI at fu(0.5) = 0.76) and antagonism in CH1 (moderate p-AKT), HX62 cells (low p-AKT), and KB cells (low p-AKT/overexpressed EGFR; CI at fu(50) = 3.0, 3.5, and 2.0, respectively). The observed effects correlated with changes in the rate of apoptosis induction. 17-AAG induced a decrease in HSP90 client proteins (e.g., C-RAF, ERBB2, and p-AKT) or in downstream markers of their activity (e.g., phosphorylated extracellular signal-regulated kinase or p-AKT) in SKOV-3, IGROV-1, and CH1 cells at IC50 concentrations. A non-growth-inhibitory concentration (6 nmol/L) reduced the phosphorylation of AKT (but not extracellular signal-regulated kinase) and sensitized SKOV-3 cells to paclitaxel. In conclusion, 17-AAG may sensitize a subset of ovarian cancer to paclitaxel, particularly those tumors in which resistance is driven by ERBB2 and/or p-AKT.