title: YM-175 induces apoptosis of human native monocyte-lineage cells via inhibition of prenylation.
abstract: Nitrogen-containing bisphosphonates (NCBPs) have been widely used as standard supportive therapy to reduce skeletal-related events (SREs) in myeloma patients through suppression of osteoclast activity. In various prospective randomized trials that were performed following preliminary reports concerning efficacy, NCBPs have shown a significant beneficial effect on myeloma bone disease through both suppression of bone resorption and direct antimyeloma activity. Thus, NCBPs have an influence on many types of human cells. In this study, we examined the effect of an NCBP (YM-175) on an apoptosis of a monocytic cell line and of human native monocytes/macrophages and dendritic cells (DCs). We confirmed that monocytes, monocyte-derived macrophages, DCs, and a monoblastic cell line (THP-1) showed dose-dependent and time-dependent apoptosis related to the activation of caspases after exposure to YM-175 at concentrations below that at which the apoptosis of myeloma cell lines was induced. Such apoptosis of monocytic cells was suppressed by the addition of farnesol or geranylgeraniol. These findings suggest that the inhibition of monocyte-lineage cells or DCs by NCBPs might interfere with phagocytic activity or pathogen-presenting activity.
authors.affiliation: Department of Hematology, National Center for Global Health and Medicine, Shinjyuku-ku, Tokyo 162-8655, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Miwa
authors.forename: Naoki
authors.initials: N
authors.lastname: Takezako
authors.forename: Hiroko
authors.initials: H
authors.lastname: Hayakawa
authors.forename: Morisada
authors.initials: M
authors.lastname: Hayakawa
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Tominaga
authors.forename: Ken
authors.initials: K
authors.lastname: Yanagisawa
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000494:pharmacology*; D006801:Humans; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009101:Multiple Myeloma; D054876:Prenylation / Q000187:drug effects*
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; C071542:cimadronate