Saito Akira, Saito Noriko, Mol William, Furukawa Hiroshi, Tsutsumida Arata, Oyama Akihiko, Sekido Mitsuru, Sasaki Satoru, Yamamoto Yuhei
Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, Hokkaido University, Kita-ku, Sapporo, Japan.
Melanoma Res. 2008 Apr;18(2):85-94. doi: 10.1097/CMR.0b013e3282f60097.
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 G1 arrest in G361 and MMAc cells. Consistent with the cell cycle arrest, simvastatin caused an increase in the mRNA levels of p21 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.
3-羟基-3-甲基戊二酰辅酶A还原酶竞争性抑制剂（他汀类药物）可抑制甲羟戊酸的合成，广泛用于治疗高胆固醇血症。尽管已有报道称他汀类药物对多种细胞类型具有抗肿瘤作用，但辛伐他汀（一种他汀类药物）对人黑色素瘤细胞系的作用尚不清楚。在此，我们报告了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A375M、G361、C8161、GAK和MMAc 1至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、形态变化、香叶基香叶基焦磷酸和法尼基焦磷酸抑制的可逆性、细胞凋亡和细胞周期。辛伐他汀处理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。在辛伐他汀存在的情况下，向A375M和G361细胞中添加香叶基香叶基焦磷酸可完全恢复细胞活力，但添加法尼基焦磷酸则不能。DNA片段化分析表明，辛伐他汀可诱导A375M和G361细胞凋亡。辛伐他汀导致G361和MMAc细胞出现G1期阻滞。与细胞周期阻滞一致，辛伐他汀导致G361和MMAc细胞中p21和p27的mRNA水平升高。我们得出结论，辛伐他汀在体外对人黑色素瘤细胞具有抗肿瘤作用，其机制是通过诱导细胞凋亡和细胞周期阻滞。这些结果表明，辛伐他汀可能是一种有效的恶性黑色素瘤抗癌药物。
