In vitro and in vivo study of cell growth inhibition of simvastatin on chronic myelogenous leukemia cells.
BACKGROUND
Statins, a family of 3-hydroxy-3-methylglutaryl CoA (HMG CoA) reductase inhibitors, are being investigated for the therapy and prevention of cancers. Here we aimed to investigate the effects of simvastatin on chronic myelogenous leukemia (CML) cells in vitro and in vivo, and to elucidate the mechanisms.


METHODS
Cell proliferation and cell cycle were measured after K562 cells were incubated with simvastatin, and differentially expressed genes were determined by oligonucleotide microarray. Changes of 2 genes obtained by oligonucleotide microarray were validated by real-time RT-PCR, and immunohistochemistry was performed to determine expression of proliferating cell nuclear antigen (PCNA). Finally, a xenograft tumor model was constructed to evaluate the effects of simvastatin in vivo.


RESULTS
Simvastatin could inhibit K562 cell proliferation, and the inhibition rate was approximately 30% after treatment with 20 mumol/l simvastatin for 48 h. Cell cycle was arrested in G(1) phase, as shown by flow cytometry results. Fifteen downregulated, 9 upregulated cell cycle-related genes and decreased PCNA protein were observed in the presence of simvastatin. Furthermore, simvastatin exhibited impairment of xenograft tumor growth in nude mice and also blocked cell cycle in G(1) phase.


CONCLUSIONS
Simvastatin can inhibit CML cell proliferation in vitro and in vivo, and its mechanisms might be involved in cell cycle regulation.
Yang
Yong-Chang
YC
Clinical Laboratory Department, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China.
Huang
Wen-Fang
WF
Chuan
Liang-Min
LM
Xiao
Dai-Wen
DW
Zeng
Ya-Li
YL
Zhou
Ding-An
DA
Xu
Guo-Qiang
GQ
Liu
Wen
W
Huang
Bo
B
Hu
Qi
Q
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D048868:Adaptor Proteins, Signal Transducing; D009687:Nuclear Proteins; C465618:PCNP protein, human; D019821:Simvastatin