In order to investigate the anti-
tumor activity of 3-hydroxy-3-methylglutaryl
coenzyme A (
HMG-CoA) reductase inhibitors and the mechanism underlying the cell proliferation and apoptosis modulated in myeloma cells, the effects of
mevastatin, an
HMG-CoA reductase inhibitor, on cell growth, cell cycle progression and apoptosis in U266 human
multiple myeloma (MM) cell line in vitro were explored by MTT colorimetric assay, morphologic observation, flow cytometry,
DNA gel electrophoresis, and RT-PCR. The results demonstrated that
mevastatin inhibited the growth of U266 cells in time- and dose-dependent manners. Cell cycle analysis showed that U266 cells underwent G(0)/G(1) arrest under exposure to
mevastatin, but it did not affect p27 expression at both
mRNA and
protein level. Morphologic observations revealed cytoplasm shrinkage, nuclear condensation and fragmentation in
mevastatin-treated cells, and fraction of
annexin V(+)PI(-) cells increased significantly in the presence of the agent as determined by flow cytometric assay. In addition,
mevastatin caused the collapse of mitochondrial transmembrane potential (Deltapsim), induced DNA fragmentation, and down-regulated the
mRNA expression of bcl-2. The growth-inhibitory, cell cycle arresting, and proapoptotic effects of
mevastatin in U266 cells could be effectively reversed by the addition of
mevalonate (MVA), the immediate endproduct of the reaction catalyzed by
HMG-CoA reductase. It is concluded that
mevastatin suppresses proliferation by inducing G(0)/G(1) phase arrest and triggering apoptosis via down-regulation of bcl-2 and reduction of Deltapsim, which may be attributed to the inhibition of MVA pathway by
mevastatin.
Statins including
mevastatin may find their future application in the treatment of MM.