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 malig nant cells in vitro. We analyzed the effect of lovastatin on. myeloid leuke mic cell lines. Lovastatin significantly inhibited the proliferation of 7 c ell lines among II myeloid leukemic cell lines in a dose-dependent manner: In order to address the mechanism of antileukemic effect of lovastatin, cel l cycle analysis was attempted in HL-60 cells, showing that lovastatin indu ced GI nn est in HL-60 cells following 72 h of drug exposure (1.5 mu M, 5 m u M and 10 mu M) in a dose-dependent manna: Analysis of GI regulatory prote ins demonstrated that the protein levels of cyclin-dependent kinase (CDK) 5 CDK4, CDK6 and cyclin E were decreased after treatment with lovastatin (10 mu M) in a time-dependent manner, but not cyclin DI. In addition lovastati n increased the protein level of the cyclin-dependent kinase inhibitor (CDK I), p27, and markedly enhanced the binding of p27 with CDK2 and CDK4 more t han CDK6 after 24 h exposure. At higher doses of lovastatin (50 mM 100 mM, 200 mM), a significant apoptosis was observed as evidenced by FAGS 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 GI arrest in association with p27 induction a nd is an effective inducer of apoptosis in HL-60 cells.