E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition
E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition
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DOI：
10.1002/ijc.23131
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发表时间：
2008-02-01
影响因子：
6.4
通讯作者：
Asada, Makoto
中科院分区：
文献类型：
--
作者：
Matsui, Junji;Yamamoto, Yuji;Asada, Makoto
E7080是多种受体酪氨酸激酶的口服活性抑制剂，包括VEGF、FGF和SCF受体。在这项研究中，我们显示了E7080对SCF诱导的血管生成的体外抑制活性和对SCF产生的人小细胞肺癌H146细胞的体内肿瘤生长的抑制活性。E7080抑制SCF驱动的表达SCIF受体KIT的HUVEC的管形成，IC 50值为5.2 nM，与VEGF驱动的管形成几乎相同（IC 50 = 5.1 nM）。为了评估SCF/KIT信号在肿瘤血管生成中的作用，我们评估了伊马替尼（一种选择性KIT激酶抑制剂）对裸鼠H146细胞肿瘤生长的影响。伊马替尼在体外未显示出有效的抗肿瘤活性（IC 50 = 2，200 nM），因为H146细胞不表达KIT。然而，口服160 mg/kg伊马替尼明显减缓了裸鼠H146细胞的肿瘤生长，并伴有微血管密度降低。经口给予30和100 mg/kg剂量的E7080以剂量依赖性方式抑制H146细胞的肿瘤生长，并在100 mg/kg剂量下引起肿瘤消退。虽然抗VEGF抗体也减缓了肿瘤生长，但它不会导致肿瘤消退。这些结果表明，KIT信号传导在SCF产生H146细胞的肿瘤血管生成中具有作用，并且E7080由于抑制KIT和VEGF受体信号传导介导的抗血管生成活性而导致H146肿瘤消退。E7080可能在治疗产生SCF的肿瘤中提供治疗益处。(c)2007 Wiley-Liss，Inc.
E7080 is an orally active inhibitor of multiple receptor tyrosine kinases including VEGF, FGF and SCF receptors. In this study, we show the inhibitory activity of E7080 against SCF-induced angio-genesis in vitro and tumor growth of SCF-producing human small cell lung carcinoma H146 cells in vivo. E7080 inhibits SCF-driven tube formation of HUVEC, which express SCIF receptor, KIT at the IC50 value of 5.2 nM and it was almost identical for VEGF-driven one (IC50 = 5.1 nM). To assess the role of SCF/KIT signaling in tumor angiogenesis, we evaluated the effect of imatinib, a selective KIT kinase inhibitor, on tumor growth of H146 cells in nude mice. Imatinib did not show the potent antitumor activity in Vitro (IC50 = 2,200 nM), because H146 cells did not express KIT. However, oral administration of imatinib at 160 mg/kg clearly slowed tumor growth of H146 cells in nude mice, accompanied by decreased microvessel density. Oral administration of E7080 inhibited tumor growth of H146 cells at doses of 30 and 100 mg/kg in a dose-dependent manner and caused tumor regression at 100 mg/kg. While anti-VEGF antibody also slowed tumor growth, it did not cause tumor regression. These results indicate that KIT signaling has a role in tumor angiogenesis of SCF-producing H146 cells, and E7080 causes regression of H146 tumors as a result of antiangiogenic activity mediated by inhibition of both KIT and VEGF receptor signaling. E7080 may provide therapeutic benefits in the treatment of SCF-producing tumors. (c) 2007 Wiley-Liss, Inc.