Effects of insulin-like growth factor-1 receptor inhibition in mesothelioma
Effects of insulin-like growth factor-1 receptor inhibition in mesothelioma
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DOI：
10.1016/j.athoracsur.2006.04.013
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发表时间：
2006-09-01
影响因子：
4.6
通讯作者：
Kratzke, Robert A.
中科院分区：
文献类型：
--
作者：
Whitson, Bryan A.;Jacobson, Blake A.;Kratzke, Robert A.
背景恶性间皮瘤是一种预后不良的毁灭性疾病。最近的数据表明，胰岛素样生长因子-1受体（IGF-1 R）可能在致癌信号中发挥作用。我们的目的是评估一种新的IGF-1 R抑制剂NVP-AEW 541对细胞生长和IGF相关通路的影响。恶性间皮瘤细胞系，H2373和H2461，以前显示激活IGF途径生长在培养基中。贴壁细胞最初以5 × 105细胞/板接种，用不同浓度的NVP-AEW 541（0、1、5、10、20和50 μ M）处理72小时，一式三份。每24小时计数活细胞。另外，将无血清培养基中的单独培养物用NVP-AEW 541处理，然后用IGF刺激并收集裂解物用于免疫印迹分析。在这两种细胞系中，0，1，5，和10 μ M显示出抑制或静态效果，而20和50 μ M的杀。免疫印迹分析表明，NVP-AEW 541在较高浓度下抑制IGF-1 R的磷酸化。IGF通路下游介质丝裂原活化蛋白激酶和Akt的磷酸化也被药物治疗所抑制。NVP-AEW 541对培养的间皮瘤细胞具有浓度依赖性抑制作用。NVP-AEW 541通过抑制IGF-1 R磷酸化起作用。抑制作用以剂量依赖性方式影响下游介质的磷酸化。IGF途径的抑制降低间皮瘤细胞培养物的活力。NVP-AEW 541和其他选择性IGF-1 R抑制剂的进一步评估可能在恶性间皮瘤的多模式治疗中发挥重要作用。
Background. Malignant mesothelioma is a devastating disease with a poor prognosis. Recent data have shown that insulin-like growth factor-1 receptor (IGF-1R) may play a role in oncogenic signaling. Our aim was to evaluate the effect of a novel IGF-1R inhibitor, NVP-AEW541, on cell growth and IGF associated pathways.Methods. Malignant mesothelioma cell lines, H2373 and H2461, previously shown to activate the IGF pathway were grown in culture. The adherent cells, initially plated at 5 x 105 cells/plate, were treated for 72 hours, in triplicate, with varying concentration of NVP-AEW541 (0, 1, 5, 10, 20, and 50 mu M). Viable cells were counted every 24 hours. Additionally, separate cultures in serum-free medium were treated with NVP-AEW541, then stimulated with IGF and lysates collected for immunoblot analysis.Results. In both cell lines, 0, 1, 5, and 10 mu M showed an inhibitory or static effect, while 20 and 50 mu M were cidal. Immunoblot analysis demonstrated that phosphorylation of IGF-1R was inhibited by NVP-AEW541 at higher concentration. Phosphorylation of mitogen-activated protein kinase and Akt, downstream IGF pathway mediators, were also shown to be repressed by drug treatment.Conclusions. NVP-AEW541 has a concentration-dependent inhibitory effect on mesothelioma cells in culture. NVP-AEW541 acts by inhibition of IGF-1R phosphorylation. Inhibition effects phosphorylation of downstream mediators in a dose-dependent fashion. Inhibition of the IGF pathway decreases viability of mesothelioma cell culture. Further evaluation of NVP-AEW541, and other selective IGF-1R inhibitors, may play an important role in multimodal treatment of malignant mesothelioma.