Yokozaki H, Ito R, Ono S, Hayashi K, Tahara E
First Department of Pathology, Hiroshima University School of Medicine, Japan.
Cancer Lett. 1999 Jun 1;140(1-2):121-8. doi: 10.1016/s0304-3835(99)00061-0.
Vesnarinone (OPC-8212; 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone ) is a synthetic oral cardiotonic agent that has been used for the treatment of patients with congestive heart failure. Six days of treatment with 30 microg/ml of vesnarinone induced 20-80% growth inhibitions in five out of six gastric carcinoma cell lines examined. Cell cycle analysis revealed that the vesnarinone-sensitive TMK-1 gastric cancer cell line exhibited a significant G0-G1 arrest without evidence of apoptotic cell death induction after 48 h of treatment. Interestingly, this phenomenon was preceded by a marked reduction in the expression of cyclin A, D1 and E as well as cyclin-dependent kinase 2 (CDK2). On the other hand, no significant change was observed in the expression of p21(Waf1/Cip1), p27Kip1 nor various growth factors and their receptor genes. Overall these results indicate that vesnarinone inhibits the growth of gastric cancer cells by down-regulating G1 cyclins and CDK2 to induce G0-G1 arrest through a pathway different from that of cyclin inactivation by p21(Waf1/Cip1) or p27Kip1.
维司力农（OPC - 8212；3,4 - 二氢 - 6 - [4 - (3,4 - 二甲氧基苯甲酰基)-1 - 哌嗪基]-2(1H)-喹啉酮）是一种合成的口服强心剂，已用于治疗充血性心力衰竭患者。用30微克/毫升维司力农处理6天，在所检测的6种胃癌细胞系中有5种出现了20 - 80%的生长抑制。细胞周期分析显示，对维司力农敏感的TMK - 1胃癌细胞系在处理48小时后出现显著的G0 - G1期阻滞，且无凋亡细胞死亡诱导的证据。有趣的是，这一现象之前，细胞周期蛋白A、D1和E以及细胞周期蛋白依赖性激酶2（CDK2）的表达显著降低。另一方面，p21（Waf1/Cip1）、p27Kip1以及各种生长因子及其受体基因的表达未观察到显著变化。总体而言，这些结果表明，维司力农通过下调G1期细胞周期蛋白和CDK2，通过一条不同于p21（Waf1/Cip1）或p27Kip1使细胞周期蛋白失活的途径来诱导G0 - G1期阻滞，从而抑制胃癌细胞的生长。
