title: Generation of reactive oxygen species is required for bucillamine, a novel anti-rheumatic drug, to induce apoptosis in concert with copper.
abstract: Rheumatoid arthritis (RA) is considered to be a proliferative disorder of synovial tissue, which is composed of macrophage-like, fibroblast-like and dendritic cells. Bucillamine (BUC) is a novel disease-modifying anti-rheumatic drug, which is a structural analogue of cysteine. Some of the pharmacological actions of BUC have been shown to depend on the generation of reactive oxygen species (ROS) in the presence of copper. In this study, we examined whether BUC in concert with copper can induce apoptosis via generation of ROS. THP.1, a human monocytic cell line, was used as surrogate for synovial cells. We observed that BUC plus copper can induce THP.1 to undergo apoptosis, as evidenced by the presence of DNA degradation, which is preceded by ROS generation and increase in membrane permeability. Moreover, catalase rescued THP.1 from BUC-mediated cell death, indicating that generation of ROS is essential for the induction of apoptosis Red blood cells (RBC), probably acting as a scavenger of ROS, also rescued THP.1 from cell death mediated by BUC plus copper. Collectively, we suggest that ROS derived from BUC in the presence of copper may suppress the outgrowth of rheumatoid arthritis synovial cells in vivo through the induction of apoptosis.
authors.affiliation: Department of Medicine and Physical Therapy, University of Tokyo School of Medicine, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sawada
authors.forename: S
authors.initials: S
authors.lastname: Hashimoto
authors.forename: H
authors.initials: H
authors.lastname: Furukawa
authors.forename: S
authors.initials: S
authors.lastname: Tohma
authors.forename: T
authors.initials: T
authors.lastname: Inoue
authors.forename: K
authors.initials: K
authors.lastname: Ito
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D003300:Copper / Q000494:pharmacology*; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D017382:Reactive Oxygen Species; D003300:Copper; D003545:Cysteine; C026535:bucillamine