[In vitro effects of mevastatin on the proliferation and apoptosis in human multiple myeloma cell line U266].
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.
Liu
Ze-Lin
ZL
Department of Hematology, The Second Hospital, Hebei Medical University, Shijiazhuang 050000, China.
Luo
Jian-Min
JM
Dong
Zuo-Ren
ZR
Wang
Fu-Xu
FX
Zhang
Xue-Jun
XJ
Yang
Jing-Ci
JC
Du
Xing-Yan
XY
Yao
Li
L
D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D016193:G1 Phase / Q000187:drug effects; D019254:Genes, bcl-2; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C012258:mevastatin; D008148:Lovastatin