title: Influence of a survivin suppressor YM155 on the chemoresistance of canine histiocytic sarcoma cells.
abstract: Histiocytic sarcoma (HS) in dogs exhibits aggressive biological behaviors and currently few effective treatments are available. Survivin could serve as a potential therapeutic target in several cancers. Sepantronium bromide (YM155) is a potential novel survivin-targeting agent and in this study the influence of survivin expression on clinical outcomes and the effects of YM155 on biological activities in HS cells were investigated. Specimens of HS dogs (n = 30) and four canine HS cell lines were used. The correlation between survivin expression and clinical outcome in the HS dogs was retrospectively assessed using quantitative PCR. Following YM155 treatment of cell lines, apoptosis, cell viability, and drug transporter activities were evaluated using annexin V staining, methylthiazole tetrazolium assays, and Hoechst-33342 staining, respectively. Elevated survivin expression in the HS dogs corresponded with reduced disease-free intervals and survival time, and increased chemoresistance, which led to poor clinical outcomes. Furthermore, YM155 treatment suppressed cell-growth and resistance to lomustine in HS cells by inhibiting the activity of ATP-binding cassette transporters. The evidence presented here supports favorable preclinical evaluation and indicates that survivin-targeted therapies might be effective against HS dogs.
authors.affiliation: Laboratory of Veterinary Surgery, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita-ku, N18 W9, Sapporo, Hokkaido 060-0818, Japan; Veterinary Teaching Hospital, Joint Faculty of Veterinary Medicine, Kagoshima University, 1-21-24 Korimoto, Kagoshima-shi, Kagoshima 890-0065, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yamazaki
authors.affiliation: Veterinary Teaching Hospital, Graduate School of Veterinary Medicine, Hokkaido University, Kita-ku, N18 W9, Sapporo, Hokkaido 060-0818, Japan. Electronic address: staka@vetmed.hokudai.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takagi
authors.affiliation: Laboratory of Veterinary Surgery, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita-ku, N18 W9, Sapporo, Hokkaido 060-0818, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Hosoya
authors.affiliation: Laboratory of Veterinary Surgery, Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Kita-ku, N18 W9, Sapporo, Hokkaido 060-0818, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Okumura
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004283:Dog Diseases / Q000188:drug therapy*; D004285:Dogs; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D054747:Histiocytic Sarcoma / Q000188:drug therapy / Q000662:veterinary*; D007093:Imidazoles / Q000627:therapeutic use*; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000627:therapeutic use; D008130:Lomustine / Q000627:therapeutic use; D008297:Male; D009285:Naphthoquinones / Q000627:therapeutic use*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D008130:Lomustine; C523798:sepantronium
keywords: Chemoresistance; Dog; Histiocytic sarcoma; Survivin; YM155