Simvastatin inhibits growth via apoptosis and the induction of cell cycle arrest in human melanoma cells
Simvastatin inhibits growth via apoptosis and the induction of cell cycle arrest in human melanoma cells
复制标题
DOI：
10.1097/cmr.0b013e3282f60097
复制
发表时间：
2008-04-01
影响因子：
2.2
通讯作者：
Yamamoto, Yuhei
中科院分区：
文献类型：
--
作者：
Saito, Akira;Saito, Noriko;Yamamoto, Yuhei
抑制甲羟戊酸合成的3-羟基-3-甲基戊二酰辅酶A还原酶的竞争性抑制剂（他汀类）广泛用于治疗高胆固醇血症。虽然他汀类药物对多种细胞类型的抗肿瘤作用已有报道，但辛伐他汀（他汀类药物之一）对人黑色素瘤细胞系的作用尚不清楚。在这里，我们报告辛伐他汀对人黑色素瘤细胞系的抗肿瘤作用。我们用不同浓度的辛伐他汀处理人黑色素瘤细胞系A375 M、G361、C8161、GAK和MMAc 1 - 3天。为了研究辛伐他汀的抗肿瘤作用，我们分析了细胞活力、形态学变化、香叶基香叶基焦磷酸和法呢基焦磷酸抑制的可逆性、凋亡和细胞周期。辛伐他汀治疗降低了所有五种黑色素瘤细胞系的细胞活力。然而，不同的黑色素瘤细胞系对辛伐他汀表现出不同的敏感性。在辛伐他汀存在下，向A375 M和G361细胞中加入香叶基香叶基焦磷酸盐完全恢复了细胞的活力，但加入法呢基焦磷酸盐则没有。DNA片段化分析显示辛伐他汀可诱导A375 M和G361细胞凋亡。辛伐他汀引起G361和MMAc细胞的G1阻滞。辛伐他汀可诱导G361和MMAc细胞p21和p27 mRNA表达增加，与细胞周期阻滞一致，提示辛伐他汀通过诱导细胞凋亡和细胞周期阻滞发挥抗肿瘤作用。提示辛伐他汀可能是治疗恶性黑色素瘤的有效药物。
Competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (the statins) that inhibit the synthesis of mevalonic acid are in wide use for treatment of hypercholesterolemia. Although antitumor effects on a variety of cell types have been reported for statins, the effect of simvastatin (one of the statins) on human melanoma cell lines is not known. Here, we report antitumor effects of simvastatin on human melanoma cell lines. We treated human melanoma cell lines, A375M, G361, C8161, GAK, and MMAc with simvastatin in various concentrations for 1 to 3 days. To investigate the antitumor effect of simvastatin, we analyzed cell viability, morphologic changes, reversibility of inhibition by geranylgeranyl pyrophosphate and farnesyl pyrophosphate, apoptosis and the cell cycle. Simvastatin treatment reduced cell viability in all five melanoma cell lines. The different melanoma cell lines, however, displayed different sensitivities to simvastatin. The addition of geranylgeranyl pyrophosphate to A375M and G361 cells in the presence of simvastatin completely restored the viability of cells, but the addition of farnesyl pyrophosphate did not. DNA fragmentation assay showed that simvastatin induced apoptosis in A375M and G361 cells. Simvastatin caused a G, arrest in G361 and MMAc cells. Consistent with the cell cycle arrest, simvastatin caused an increase in the mRNA levels of p2l and p27 on G361 and MMAc cells.We conclude that simvastatin has an antitumor effect on human melanoma cells in vitro via apoptosis and cell cycle arrest. These results suggest that simvastatin may be an effective anticancer drug for malignant melanoma.