Double blockade of cell cycle progression by coptisine in vascular smooth muscle cells.
Double blockade of cell cycle progression by coptisine in vascular smooth muscle cells.
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DOI：
10.1016/j.bcp.2005.07.010
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发表时间：
2005-10
影响因子：
5.8
通讯作者：
H. Tanabe;H. Suzuki;H. Mizukami;M. Inoue
中科院分区：
文献类型：
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作者：
H. Tanabe;H. Suzuki;H. Mizukami;M. Inoue
黄连碱是从黄连根茎中分离得到的一种异喹啉生物碱，具有抑制血管平滑肌细胞增殖的作用。本研究的目的是评估黄连碱，沿着与小檗碱（一种结构相似的异喹啉生物碱）对VSMCs细胞周期进程的作用。黄连碱通过阻滞细胞周期于G1期和G2/M期而抑制血管平滑肌细胞增殖。当黄连碱浓度高于15μM时，[3 H]胸苷掺入VSMCs受到抑制，表现为G1阻滞。G1期阻滞的机制涉及细胞周期蛋白D1蛋白的减少，尽管细胞周期蛋白E、A和B不受黄连碱处理的影响。细胞周期蛋白D1蛋白的选择性减少主要归因于通过蛋白酶体依赖性途径加速蛋白质水解，因为它被蛋白酶体抑制剂N-苄氧羰基-l-亮氨酰-l-亮氨酰-l-正亮氨醛（MG 132）抑制，并且进一步细胞周期蛋白D1的mRNA水平、蛋白质合成和有丝分裂原活化蛋白激酶（MAPK）活性保持不变。G2/M期阻滞的机制涉及微管蛋白聚合的部分抑制，这在黄连碱浓度为3μM时是明显的。小檗碱可使细胞周期阻滞于G1期，但不能阻滞于G2/M期。结果表明，异喹啉生物碱之间结构上的微小差异会产生很大的活性差异，并且黄连碱在阻滞VSMC细胞周期方面具有独特的双重作用。
Coptisine, an isoquinoline alkaloid isolated from rhizome of Coptis japonica, inhibits proliferation of vascular smooth muscle cells (VSMCs). The aim of this study was to evaluate the action of coptisine, along with berberine (a structurally similar isoquinoline alkaloid), on progression of the cell cycle in VSMCs. Coptisine displayed antiproliferative action against VSMCs by blocking the cell cycle at G1and G2/M phases. The G1block was shown by inhibition of [3H]thymidine incorporation into VSMCs at coptisine concentrations higher than 15μM. The mechanism underlying the G1arrest involved a decrease in cyclin D1 protein, although cyclin E, A, and B were not affected by coptisine treatment. The selective reduction in cyclin D1 protein was mainly attributable to accelerated proteolysis via proteasome-dependent pathway, since it was inhibited by a proteasome inhibitor, N-carbobenzoxy-l-leucinyl-l-leucinyl-l-norleucinal (MG132) and further the mRNA level of cyclin D1, protein synthesis, and mitogen-activated protein kinase (MAPK) activity remained unaltered. The mechanism underlying the G2/M arrest involved partial inhibition of tubulin polymerization, which was apparent at coptisine concentration of 3μM. Berberine arrested the cell cycle at G1phase via a mechanism identical with coptisine, but did not cause block at G2/M phase. The results demonstrate that a small difference in the structure between isoquinoline alkaloids produces a big difference in activity, and that coptisine has a unique double action in arresting the cell cycle of VSMCs.