RRC ID 41975
Author Nishida S, Fujii Y, Yoshioka S, Kikuichi S, Tsubaki M, Irimajiri K.
Title A new bisphosphonate, YM529 induces apoptosis in HL60 cells by decreasing phosphorylation of single survival signal ERK.
Journal Life Sci
Abstract It is believed that bisphosphonates (BPs) induce apoptosis in cells such as myeloma cells, as they inhibit prenylation of G-proteins. However, the details of the apoptosis-inducing mechanism remain obscure. In the present study, we attempted to clarify the mechanism by which YM529, a new bisphosphonate, induces apoptosis. YM529 induced cell deaths in HL60 cells in a concentration-dependent manner. At that time, we observed an increase in Caspase-3 activity and morphological fragmentation of the nuclei. We could confirm that these cell deaths were evidence of apoptosis. The apoptosis induced by YM529 was not inhibited by the addition of farnesyl pyrophosphate (FPP), but was by the addition of geranylgeranyl pyrophosphate (GGPP). When we examined the survival signals at the time of apoptotic induction, we also observed that the administration of YM529 caused a remarkable decrease in the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). However, other survival signals such as nuclear factor kappa B (NF-kappaB), protein kinase B (Akt), and p38 mitogen-activated protein kinase (p38) exhibited no change. In addition, no quantitative change was observed in Bcl-2, which is an anti-apoptosis protein. It was also observed that apoptosis was induced when U0126, an MEK inhibitor, was added to the cells to inhibit ERK. These results suggest that YM529, the new bisphosphonate, induced apoptosis when inhibit GGPP synthase and consequently decreased the levels of phosphorylated ERK, which is a survival signal; moreover, during this process, there is no influence on NF-kappaB, Akt, p38, and Bcl-2. The results of this study also suggest that YM529 can be used as an anticancer agent, in addition to its use as a therapeutic agent to treat osteoporosis.
Volume 73(21)
Pages 2655-64
Published 2003-10-10
DOI 10.1016/s0024-3205(03)00664-7
PII S0024320503006647
PMID 13679234
MeSH Apoptosis / drug effects* Butadienes / pharmacology Caspase 3 Caspases / metabolism Cell Survival / drug effects Diphosphonates / pharmacology* Dose-Response Relationship, Drug Drug Antagonism Drug Combinations Enzyme Inhibitors / pharmacology HL-60 Cells / drug effects* HL-60 Cells / metabolism HL-60 Cells / pathology Humans Imidazoles / pharmacology* Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinases / antagonists & inhibitors Mitogen-Activated Protein Kinases / metabolism* Nitriles / pharmacology Phosphorylation Polyisoprenyl Phosphates / pharmacology
IF 3.448
Times Cited 31
Human and Animal Cells