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.

Regulation of apoptosis in human melanoma and neuroblastoma cells by statins, sodium arsenite and TRAIL: a role of combined treatment versus monotherapy

“…Our observations and published data also demonstrated that monotreatment with statin induced pronounced apoptotic death in some melanoma cell lines only at relatively high doses (5–20 μM) [44]. Animal experiments with the B16F10 mouse melanoma model exhibited a suppression of tumor growth by treatment with 1.6 μM simvastatin [45].…”

“…Even though proapoptotic effects of statins for melanoma cells have been previously reported in several publications [44, 55, 56], sensitization of melanoma cells to TRAIL-induced apoptosis by statins, which was investigated in our study, potentially could be a new modality for melanoma therapy. It was especially important, that combined treatment of statin and TRAIL was also quite effective for killing BRAF wt melanoma cell lines, such as WM852 and FEMX (see Fig.…”

Can statin therapy reduce the risk of melanoma? A meta-analysis of randomized controlled trials

“…Despite promising findings stemming from in vitro and animal studies [3][4][5][6][7][8][9], the present quantitative synthesis of 16 RCTs provides no evidence for an association between statin use and the risk of melanoma. Our results are in accord with recent metaanalyses on the association between statin use and other site-specific cancers.…”

“…In vitro and animal studies have supported a potential protective role of statins through pleiotropic antiinflammatory, immunomodulatory, and antiangiogenesis mechanisms. In particular, statins have been shown to induce melanoma cell apoptosis, to inhibit proliferation and invasion, and to prevent activation of key proteins for cell cycle regulation [3][4][5][6][7][8][9].…”

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

“…This effect was mediated by direct interference with RAS functions (Grana et al, 2002) and G 1 arrest of the cell cycle (Sivaprasad et al, 2006;Saito et al, 2008;Javanmoghadam-Kamrani and Keyomarsi., 2008), in addition to the arrest in G 2 phase induced by radiation.…”