Department of Biomedical Sciences and NCEED, College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea.
Cancer Lett. 2013 May 10;332(1):74-82. doi: 10.1016/j.canlet.2013.01.015. Epub 2013 Jan 21.
Among many cancer therapeutic targets, c-Met receptor tyrosine kinase has recently given particular attention. This kinase and its ligand, hepatocyte growth factor (HGF), play a central role in cell proliferation and the survival of several human cancers. Thus, we developed KRC-408 as a novel c-Met inhibitor and investigated its anti-cancer effects on human gastric cancer. KRC-408 inhibited the phosphorylation of c-Met and its constitutive downstream effectors such as phosphatidylinositol 3-kinase (PI3K), Akt, Mek, and Erk. This compound was found to exert anti-cancer effects stronger than those of 5-fluorouracil (5-FU) on gastric cancer cells, especially cell lines that overexpressed c-Met. Interestingly, cytotoxicity of KRC-408 was lower than that of 5-FU in normal gastric cells. Apoptosis induced by KRC-408 was accompanied by increased levels of cleaved caspase-3 and PARP as well as DNA condensation and fragmentation. Flow cytometry analysis showed an accumulation of gastric cancer cells in the G2/M phase with concomitant loss of cells in the S phase following treatment with this drug. In the angiogenesis studies, KRC-408 inhibited tube formation and migration of human umbilical vein endothelial cells (HUVECs), and suppressed microvessel sprouting from rat aortic rings ex vivo along with blood vessel formation in a Matrigel plug assay in mice. Results of an in vivo mouse xenograft experiment showed that the administration of KRC-408 significantly delayed tumor growth in a dose-dependent manner, and suppressed Akt and Erk phosphorylation as well CD34 expression in tumor tissues. These findings indicate that KCR-408 may exert anti-tumor effects by directly affecting tumor cell growth or survival via the c-Met receptor tyrosine kinase pathway. We therefore suggest that KRC-408 is a novel therapeutic candidate effective against gastric cancers that overexpress c-Met.
在众多癌症治疗靶点中，c-Met 受体酪氨酸激酶最近受到了特别关注。这种激酶及其配体肝细胞生长因子（HGF）在细胞增殖和几种人类癌症的存活中起着核心作用。因此，我们开发了 KRC-408 作为一种新型的 c-Met 抑制剂，并研究了它对人类胃癌的抗癌作用。KRC-408 抑制 c-Met 的磷酸化及其组成性下游效应物，如磷脂酰肌醇 3-激酶（PI3K）、Akt、Mek 和 Erk。该化合物被发现对胃癌细胞具有比 5-氟尿嘧啶（5-FU）更强的抗癌作用，特别是那些过表达 c-Met 的细胞系。有趣的是，KRC-408 的细胞毒性比 5-FU 在正常胃细胞中低。KRC-408 诱导的细胞凋亡伴随着 cleaved caspase-3 和 PARP 水平的增加以及 DNA 凝聚和片段化。流式细胞术分析显示，胃癌细胞在 G2/M 期积累，同时 S 期细胞丢失，用该药物处理后。在血管生成研究中，KRC-408 抑制人脐静脉内皮细胞（HUVEC）的管形成和迁移，并抑制大鼠主动脉环的微血管发芽以及在小鼠中的 Matrigel 塞中血管形成。体内小鼠异种移植实验的结果表明，KRC-408 以剂量依赖的方式显著延迟肿瘤生长，并抑制肿瘤组织中的 Akt 和 Erk 磷酸化以及 CD34 表达。这些发现表明，KCR-408 可能通过直接影响肿瘤细胞生长或通过 c-Met 受体酪氨酸激酶途径存活来发挥抗肿瘤作用。因此，我们认为 KRC-408 是一种有效的新型治疗候选药物，可有效对抗过表达 c-Met 的胃癌。
