Activity of the multikinase inhibitor dasatinib against ovarian cancer cells.
Activity of the multikinase inhibitor dasatinib against ovarian cancer cells.
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DOI：
10.1038/sj.bjc.6605381
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发表时间：
2009-11-17
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
在这里，我们探讨了达沙替尼的治疗潜力，这是一种小分子抑制剂，靶向多种细胞溶质和膜结合酪氨酸激酶，包括Src激酶家族成员，EphA 2和黏着斑激酶，用于治疗卵巢癌。我们使用一组34个已建立的人卵巢癌细胞系，研究了达沙替尼对增殖、侵袭、凋亡、细胞周期阻滞和激酶活性的影响。使用基因表达谱研究了用于反应预测的分子标记。多药效应/联合指数（CI）等效线图分析用于研究与化疗药物的相互作用。在所有检测的卵巢癌细胞系中均观察到达沙替尼的浓度依赖性抗增殖作用，但个体细胞系之间差异显著，IC 50值差异高达3倍对数（IC 50范围：0.001-11.3 μmol l−1）。达沙替尼显著抑制细胞侵袭，诱导细胞凋亡，但细胞周期阻滞较少。在广泛的临床可达到的药物浓度范围内，观察到达沙替尼+卡铂（平均CI值，范围：0.73-1.11）或紫杉醇（平均CI值，范围：0.76-1.05）的相加和协同相互作用。在这项研究中，34种代表性卵巢癌细胞系中有24种（71%）对达沙替尼高度敏感，而之前报道的39种代表性乳腺癌细胞系中只有8种（21%）对达沙替尼高度敏感。高表达Yes、林恩、Eph 2A、小窝蛋白-1和2、膜突蛋白、膜联蛋白-1和uPA的细胞系对达沙替尼特别敏感。这些数据提供了一个明确的生物学原理，以测试达沙替尼作为单一药物或与化疗联合治疗卵巢癌患者。
Here, we explore the therapeutic potential of dasatinib, a small-molecule inhibitor that targets multiple cytosolic and membrane-bound tyrosine kinases, including members of the Src kinase family, EphA2, and focal adhesion kinase for the treatment of ovarian cancer. We examined the effects of dasatinib on proliferation, invasion, apoptosis, cell-cycle arrest, and kinase activity using a panel of 34 established human ovarian cancer cell lines. Molecular markers for response prediction were studied using gene expression profiling. Multiple drug effect/combination index (CI) isobologram analysis was used to study the interactions with chemotherapeutic drugs. Concentration-dependent anti-proliferative effects of dasatinib were seen in all ovarian cancer cell lines tested, but varied significantly between individual cell lines with up to a 3 log-fold difference in the IC50 values (IC50 range: 0.001–11.3 μmol l−1). Dasatinib significantly inhibited invasion, and induced cell apoptosis, but less cell-cycle arrest. At a wide range of clinically achievable drug concentrations, additive and synergistic interactions were observed for dasatinib plus carboplatin (mean CI values, range: 0.73–1.11) or paclitaxel (mean CI values, range: 0.76–1.05). In this study, 24 out of 34 (71%) representative ovarian cancer cell lines were highly sensitive to dasatinib, compared with only 8 out of 39 (21%) representative breast cancer cell lines previously reported. Cell lines with high expression of Yes, Lyn, Eph2A, caveolin-1 and 2, moesin, annexin-1, and uPA were particularly sensitive to dasatinib. These data provide a clear biological rationale to test dasatinib as a single agent or in combination with chemotherapy in patients with ovarian cancer.
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受体酪氨酸激酶EPHB4在卵巢癌中过表达，提供生存信号并预测结果不佳。
影响因子：
8.8
作者：
Kumar, S. R.;Masood, R.;Spannuth, W. A.;Singh, J.;Scehnet, J.;Kleiber, G.;Jennings, N.;Deavers, M.;Krasnoperov, V.;Dubeau, L.;Weaver, F. A.;Sood, A. K.;Gill, P. S.
通讯作者：
Gill, P. S.
影响因子：
3.5
作者：
Schütt, BS;Langkamp, M;Elmlinger, MW
通讯作者：
Elmlinger, MW
影响因子：
10.3
作者：
Pegram, MD;Konecny, GE;Slamon, DJ
通讯作者：
Slamon, DJ
影响因子：
4.8
作者：
Bailey, Kelly M.;Liu, Jun
通讯作者：
Liu, Jun
影响因子：
11.2
作者：
Huang, Fei;Reeves, Karen;Clark, Edwin
通讯作者：
Clark, Edwin