Prevention of hepatic carcinogenesis and treatment of hepatoma by way of inhibition of the activation of Ras oncogene

抑制Ras癌基因激活预防肝癌和治疗肝癌

• 批准号: 07670599
• 负责人: SAKAI Hironori
• 金额: $ 1.54万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07670599/
• 关键词: Ras Protein; HMG-CoA Reductase Inibiter; Hepatoma; 肝細胞癌; ras蛋白; HMG-CoA reductase阻害剤; メバロン酸

HMG-CoA reductase inhibiters inhibit the mevalonic pathway and then regulate the function of Ras protein. We tried to exhibit that they were able to inhibit the growth of hepatocyte and some kinds of hepatoma cell lines and that they had the possible therapeutic effect on hepatocellular carcinoma.1. Simvastasin inhibited the growth of hepatoma cell lines (Hep G2, HuH-7, HLE, PLC/PRF/5) as a dose dependent manner. The extents of inhibition of growth were all most same among these cell lines.2. Pravastatin did not have inhibitory effects of growth of all these cell lines. Since hepatoma cell lines did not have anion transporter system to transfer pravastatin into cells, pravastatin failed to inhibit the growth of these cells.3. The inhibitory effect of simvastatin on hepatoma cell growth was nearly prevented in the presence of sufficient amount of exogenous mevalonic acid. So it was obvious that the mevalonic pathway was required for the growth of these cell lines. But neither farnesol nor isopentenyl adenine prevented the simvastatin induced inhibition of the growth of these cell lines.4. Clinical trial of HMG-CoA reductase inhibiter administrated to patients with hepatocellular carcinoma revealed that simvastatin possibly had a therapeutic effects but pravastatin did not have.

HMG-CoA还原酶抑制剂通过抑制甲羟戊酸途径，调节Ras蛋白的功能。本研究试图证明它们能抑制肝细胞和某些肝癌细胞株的生长，并对肝癌有可能的治疗作用.辛伐他汀对人肝癌细胞株Hep G2、HuH-7、HLE、PLC/PRF/5的生长有抑制作用，并呈剂量依赖性。这些细胞株的生长抑制程度基本相同.普伐他汀对所有这些细胞株的生长均无抑制作用。由于肝癌细胞系不具备将普伐他汀转运入细胞的阴离子转运系统，普伐他汀不能抑制肝癌细胞的生长.在足够量的外源性甲羟戊酸存在下，辛伐他汀对肝癌细胞生长的抑制作用几乎被阻断。因此，很明显，这些细胞系的生长需要甲羟戊酸途径。但法尼醇和异戊烯基腺嘌呤均不能阻止辛伐他汀对这些细胞株生长的抑制作用.应用HMG-CoA还原酶抑制剂治疗肝癌的临床试验表明，辛伐他汀可能有治疗作用，而普伐他汀无此作用。

项目成果

Takeaki Satoh et al.: "The effects of pravastatin,an HMG-CoA reductase inhibitor,on cell viability and DNA production of rat hepatocytes" Life Sciences. 59・14. 1103-1108 (1996)

Takeaki Satoh 等：“HMG-CoA 还原酶抑制剂普伐他汀对大鼠肝细胞活力和 DNA 产生的影响”生命科学 59·14（1996）。