Basic research on anti-tumor effects of Interferon-α on hepatocellular carcinoma

干扰素-α抗肝癌作用的基础研究

基本信息

批准号：
13670233
负责人：
YANO Hirohisa
金额：
$ 1.92万
依托单位：
KURUME UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

[Purpose] In this study, we examined that the effects of IFN-α subtypes on the growth of human liver cancer cell lines in vitro ; growth inhibitory effects of IFN-α and 5-Fu in vitro ; mechanisms of apoptosis induction by IFN-α; and the effects of IFN-α alone or IFN-α plus 5-Fu on the growth of human liver cancer cell lines transplanted In nude mice.[Results] 1. When we examined the effects of five kinds of recombinant IFN-α subtypes (α1, α2, α5, α8, α10; concentrations: 0-1024 IU/mL; 24-96 hours) on the growth of 13 human liver cancer cell lines, the strongest anti-proliferative effects was noted In IFN-α5 subtype, and followed by α8, α10, α2, α1. 2. No synergistic growth Inhibitory effects could be recognized when IFN-α and 5-Fu were simultaneously added t o the culture of liver cancer cells. 3. Natural human IFN-α induced activation of caspase-3, -7, -8, and -9, and proteolysis of PARP in IFN-α-induced apoptosis-sensitive cell lines at various degrees. In addition, release of cytochrome C and Smac/Diablo from mitochondria into cytoplasm was identified in IFN-α-treated cells time-dependently. These findings suggest mitochondria apoptosis induction pathway is involved in the IFN-α-induced apoptosis. 4. Subcutaneous IFN-αCon1 injection (0.01, 0.1, 1μg/mouse/day; 0.01 μg/mouse = clinical dosesage) for consecutive 14 days dose-and time-dependently suppressed the HCC tumor growth in nude mice. Finally, the tumor volumes of mice received 0.01, 0.1, and 1 μg/mouse of IFN-αCon1 decreased to about 60%, 25%,and 0-10%, respectively, of control tumor volumes. The number of apoptotic cells significantly Increased and the number of blood vessels significantly decreased with the increase of IFN-αCon1 dose. 5. Synergistic effect of IFN-α plus 5-Fu was identified In nude mouse tumors. [Conclusions] These data Indicate the potential clinical application of certain types of IFN-α in the prevention and treatment of HCC.

[目的]本研究探讨IFN-α亚型对人肝癌细胞系体外生长的影响；以及IFN-α和5-Fu体外诱导细胞凋亡的机制； α；单独使用IFN-α或IFN-α联合5-Fu对裸鼠移植的人肝癌细胞系生长的影响。 [结果] 1.当我们检查五种药物的影响时重组IFN-α亚型（α1、α2、α5、α8、α10；浓度：0-1024 IU/mL；24-96小时）对13种人肝癌细胞系的生长，发现最强的抗增殖作用。 IFN-α5 亚型，其次是α8、α10、α2、α1。没有协同生长抑制作用。 3.天然人IFN-α在IFN-α诱导的凋亡敏感细胞系中不同程度地诱导caspase-3、-7、-8和-9的激活以及PARP的蛋白水解。此外，还释放细胞色素C。在 IFN-α 处理的细胞中，鉴定出 Smac/Diablo 从线粒体进入细胞质的时间依赖性。这些发现表明线粒体凋亡诱导途径。 4.皮下注射IFN-αCon1（0.01、0.1、1μg/小鼠/天；0.01μg/小鼠=临床剂量）连续14天剂量和时间依赖性抑制HCC。最后，接受 0.01、0.1 和 1 μg/只 IFN-αCon1 的小鼠的肿瘤体积。 5. IFN-α与5-Fu在裸鼠肿瘤中发现协同作用 [结论] 这些数据表明某些类型的IFN-α在预防和治疗HCC方面的潜在临床应用。