Lovastatin-induced inhibition of HL-60 cell proliferation via cell cycle arrest and apoptosis.
An inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, lovastatin, induces growth arrest and cell death in a wide variety of malignant cells in vitro. We analyzed the effect of lovastatin on myeloid leukemic cell lines. Lovastatin significantly inhibited the proliferation of 7 cell lines among 11 myeloid leukemic cell lines in a dose-dependent manner. In order to address the mechanism of antileukemic effect of lovastatin, cell cycle analysis was attempted in HL-60 cells, showing that lovastatin induced G1 arrest in HL-60 cells following 72 h of drug exposure (1.5 microM, 5 microM and 10 microM) in a dose-dependent manner. Analysis of G1 regulatory proteins demonstrated that the protein levels of cyclin-dependent kinase (CDK) 2, CDK4, CDK6 and cyclin E were decreased after treatment with lovastatin (10 microM) in a time-dependent manner, but not cyclin D1. In addition, lovastatin increased the protein level of the cyclin-dependent kinase inhibitor (CDKI), p27, and markedly enhanced the binding of p27 with CDK2 and CDK4 more than CDK6 after 24 h exposure. At higher doses of lovastatin (50 mM, 100 mM, 200 mM), a significant apoptosis was observed as evidenced by FACS analysis with annexin V staining, which was associated with downregulation of Bcl-2 protein. These results suggest that lovastatin inhibits the proliferation of myeloid leukemic cells via G1 arrest in association with p27 induction and is an effective inducer of apoptosis in HL-60 cells.
Park
W H
WH
Department of Internal Medicine, Cancer Research Center, Seoul National University College of Medicine, Korea.
Lee
Y Y
YY
Kim
E S
ES
Seol
J G
JG
Jung
C W
CW
Lee
C C
CC
Kim
B K
BK
D017209:Apoptosis / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D016193:G1 Phase / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D008148:Lovastatin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D018797:Cell Cycle Proteins; D008148:Lovastatin