State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Cancer Lett. 2013 Oct 28;340(1):88-96. doi: 10.1016/j.canlet.2013.07.005. Epub 2013 Jul 12.
Accumulating evidence suggested that the irreversible tyrosine kinase inhibitors (TKIs) have potential to override the acquired resistance to target-based therapies. Herein, we reported IC-4 as a novel irreversible TKI for epidermal growth factor receptor (EGFR). IC-4 potentially suppressed proliferation, induced apoptosis and a G2/M cell cycle arrest in breast cancer cells, correlating with inhibition of EGF-induced EGFR activation, but independent of DNA damage. In addition, IC-4 exhibited anti-angiogenetic activities both in vitro and in vivo. It suppressed cell viability and proliferation induced by various growth factors in human umbilical vein endothelial cells (HUVECs). IC-4 also inhibited HUVECs migration and tube formation. In transgenic zebrafish embryo model, IC-4 was shown to suppress formation of intersegmental vessel and development of subintestinal vessels. Taken together, these results demonstrated that IC-4 is a new irreversible EGFR-TKI, exhibiting potent anti-breast cancer and anti-angiogenetic effects.
越来越多的证据表明，不可逆的酪氨酸激酶抑制剂（TKI）有可能克服针对基于靶点的治疗的获得性耐药性。在此，我们报道了 IC-4 是一种新型的表皮生长因子受体（EGFR）不可逆 TKI。IC-4 可能抑制乳腺癌细胞的增殖，诱导细胞凋亡和 G2/M 细胞周期停滞，与抑制 EGF 诱导的 EGFR 激活相关，但与 DNA 损伤无关。此外，IC-4 在体外和体内均表现出抗血管生成活性。它抑制人脐静脉内皮细胞（HUVEC）中各种生长因子诱导的细胞活力和增殖。IC-4 还抑制 HUVEC 的迁移和管状形成。在转基因斑马鱼胚胎模型中，IC-4 被证明可抑制节间血管的形成和肠下血管的发育。综上所述，这些结果表明，IC-4 是一种新型的不可逆 EGFR-TKI，具有强大的抗乳腺癌和抗血管生成作用。
