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.