In vitro and in vivo antitumor effects of the dual insulin-like growth factor-I/insulin receptor inhibitor, BMS-554417
In vitro and in vivo antitumor effects of the dual insulin-like growth factor-I/insulin receptor inhibitor, BMS-554417
复制标题
DOI：
10.1158/0008-5472.can-05-1107
复制
发表时间：
2006-01-01
期刊：
影响因子：
11.2
通讯作者：
Erlichman, C
中科院分区：
文献类型：
--
作者：
Haluska, P;Carboni, JM;Erlichman, C
胰岛素样生长因子受体（IGF-IR）和胰岛素受体在多种肿瘤类型中过度活化和/或过表达，并导致肿瘤性，增殖，转移和耐药性。在这里，我们表明，BMS-554417是一种新型的小分子，发展为IGF-IR的抑制剂，可在体外抑制IGF-IR和胰岛素受体激酶活性和增殖，并减少体内肿瘤异种移植大小。在一系列癌细胞系中，用于增殖的IC50范围从120 nmol/L（Colo205）到> 8.5 Mu mol/L（OV202）。在MCF-7和OV202细胞中，不需要添加刺激性配体的抗增殖作用。 BMS-554417治疗通过细胞外信号相关激酶以及磷酸肌醇3-激酶/AKT途径抑制IGF-IR和胰岛素受体信号传导，473，Ser（473）证明了Akt磷酸化的降低所证明的。在抑制增殖的剂量下，该化合物还引起了GO-G，阻止并防止了Cyclin D1响应LR3-I的核积累。在Jurkat T细胞白血病细胞中，该药物通过线粒体途径触发了凋亡细胞死亡。 BMS-554417是口服生物可利用的，并显着抑制了体内IGF1R-SAL肿瘤异种移植物的生长。 BMS-554417是具有潜在临床应用的新型IGF-IR/胰岛素受体抑制剂的成员，因为它们在体外和体内具有抗增殖和促凋亡活性。
The insulin-like growth factor receptor (IGF-IR) and insulin receptor are either overactivated and/or overexpressed in a wide range of tumor types and contribute to tumorigenicity, proliferation, metastasis, and drug resistance. Here, we show that BMS-554417, a novel small molecule developed as an inhibitor of IGF-IR, inhibits IGF-IR and insulin receptor kinase activity and proliferation in vitro, and reduces tumor xenograft size in vivo. In a series of carcinoma cell lines, the IC50 for proliferation ranged from 120 nmol/L (Colo205) to >8.5 mu mol/L (OV202). The addition of stimulatory ligands was unnecessary for the antiproliferative effect in MCF-7 and OV202 cells. BMS-554417 treatment inhibited IGF-IR and insulin receptor signaling through extracellular signal-related kinase as well as the phosphoinositide 3-kinase/Akt pathway, 473 as evidenced by decreased Akt phosphorylation at Ser(473). At doses that inhibited proliferation, the compound also caused a GO-G, arrest and prevented nuclear accumulation of cyclin D1 in response to LR3-I. In Jurkat T-cell leukemia cells, this agent triggered apoptotic cell death via the mitochondrial pathway. BMS-554417 was orally bioavailable and significantly inhibited the growth of IGF1R-Sal tumor xenografts in vivo. BMS-554417 is a member of a novel class of IGF-IR/insulin receptor inhibitors that have potential clinical applications because of their antiproliferative and proapoptotic activity in vitro and in vivo.