title: Simvastatin inhibits growth via apoptosis and the induction of cell cycle arrest in human melanoma cells.
abstract: 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.
authors.affiliation: Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, Hokkaido University, Kita-ku, Sapporo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Saito
authors.forename: Noriko
authors.initials: N
authors.lastname: Saito
authors.forename: William
authors.initials: W
authors.lastname: Mol
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Furukawa
authors.forename: Arata
authors.initials: A
authors.lastname: Tsutsumida
authors.forename: Akihiko
authors.initials: A
authors.lastname: Oyama
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Sekido
authors.forename: Satoru
authors.initials: S
authors.lastname: Sasaki
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Yamamoto
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008545:Melanoma / Q000473:pathology*; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D012333:RNA, Messenger; D012717:Sesquiterpenes; D050760:Cyclin-Dependent Kinase Inhibitor p27; C015234:geranyl pyrophosphate; C004808:farnesyl pyrophosphate; D019821:Simvastatin