Suppression of tumor proliferation and angiogenesis of hepatocellular carcinoma by HS-104, a novel phosphoinositide 3-kinase inhibitor
Suppression of tumor proliferation and angiogenesis of hepatocellular carcinoma by HS-104, a novel phosphoinositide 3-kinase inhibitor
复制标题
DOI：
10.1016/j.canlet.2012.08.005
复制
发表时间：
2013-01-01
期刊：
影响因子：
9.7
通讯作者：
Hong, Soon-Sun
中科院分区：
文献类型：
--
作者：
Jung, Kyung Hee;Zheng, Hong-Mei;Hong, Soon-Sun
磷酸肌肽3-激酶(PI3K)/AKT/mTOR信号通路的失调经常引发肿瘤发生，导致肝细胞癌（HCC）。合成了一种新型PI3K抑制剂N-（5-（3-（3-甲基-1,2,4-恶二唑-3-基）咪唑[1,2-a]吡啶-6-基）吡啶-3-基）苯磺酰胺（HS-104），并在动物异种移植模型上研究了其体外抗癌作用和体内能力。HS-104对细胞生长的抑制作用表明，HS-104对肝癌细胞系有一定的抑制作用。此外，HS-104以剂量依赖的方式抑制AKT/mTOR信号级联的激活。流式细胞术分析显示HCC细胞在G2/M期积聚，同时在S期细胞减少。HS-104的凋亡作用伴随着caspase-3和PARP的断裂以及DNA断裂的增加。在血管生成研究中，HS-104抑制了血管内皮生长因子（VEGF）诱导的人脐静脉内皮细胞（HUVECs）的管状形成，并抑制了大鼠主动脉环、离体微血管的发芽，以及小鼠Matrigel塞实验中的血管形成。HS-104在vegf诱导的HUVECs中抑制PI3K下游蛋白包括p-AKT、p-mTOR和p-p70S6K的表达。在异种移植动物模型中。HS-104以剂量依赖的方式显著延缓肿瘤生长，抑制肿瘤组织中PCNA、CD34和cleaved caspase-3的表达。这些研究表明，HS-104抑制PI3K/AKT/mTOR信号通路，抑制细胞生长/血管生成，诱导细胞凋亡。因此，HS-104被认为是一种治疗HCC的新型候选药物。2012爱思唯尔爱尔兰有限公司版权所有。
Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR signaling pathway frequently instigates tumorigenesis leading to hepatocellular carcinoma (HCC). We synthesized N-(5-(3-(3-methyl-1,2,4-oxadiazol-3-yl)imidazo[1,2-a]pyridin-6-yl)pyridin-3-yl)benzenesulfonamide (HS-104), a novel PI3K inhibitor, and investigated its in vitro anticancer effect and in vivo capacity in an animal xenograft model. The inhibition of cell growth by HS-104 revealed that it was effective against HCC cell lines. Also, the activation of the AKT/mTOR signal cascade was inhibited by HS-104 treatment in a dose dependent manner. Flow cytometry analysis showed an accumulation of HCC cells in the G2/M phase with concomitant loss of cells in the S phase. The apoptotic effect of HS-104 was accompanied by increased evidence of cleaved caspase-3 and PARP, as well as DNA fragmentation. In angiogenesis studies, HS-104 inhibited the tube formation of vascular endothelial growth factor (VEGF)-induced human umbilical vein endothelial cells (HUVECs), and suppressed microvessel sprouting from a rat aortic ring, ex vivo, and blood vessel formation in the Matrigel plug assay in mice. HS-104 inhibited the expression of the downstream proteins of PI3K including p-AKT, p-mTOR and p-p70S6K in VEGF-induced HUVECs. In the xenograft animal model. HS-104 significantly delayed tumor growth in a dose dependent manner and suppressed the expression of PCNA, CD34 and cleaved caspase-3 in tumor tissue. These studies show that HS-104 inhibited the PI3K/AKT/mTOR signaling pathway resulting in cell growth/angiogenesis inhibition and apoptosis induction. Therefore, HS-104 is considered as a novel drug candidate for the treatment of HCC. (C) 2012 Elsevier Ireland Ltd. All rights reserved.