sepantronium and Histiocytic-Sarcoma

Histiocytic sarcoma (HS) in dogs exhibits aggressive clinical and biological behavior. Currently, no effective treatments are available for dogs with HS. Survivin, a member of a family of apoptosis protein inhibitors, could serve as a potential therapeutic target in several canine cancers. Sepantronium bromide (YM155) has recently been established as a novel survivin-targeting agent. The aim of this study was to use YM155 as a tool for evaluating survivin-targeted therapies against dogs with HS, and to investigate how YM155 treatment affects antitumor and chemotherapeutic efficacies in murine xenograft models using canine HS cells. The results showed that in HS cells with lomustine (CCNU) resistance, YM155 treatment suppressed both the cell-growth potential and cell resistance to CCNU, which essentially increases the chemotherapy efficacy in the murine models. The evidence presented here supports the favorable preclinical evaluation that survivin-targeted therapies might be effective against HS in dogs.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Dog Diseases; Dogs; Histiocytic Sarcoma; Imidazoles; Inhibitor of Apoptosis Proteins; Mice; Models, Animal; Naphthoquinones; Repressor Proteins; Survivin

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.

Topics: Animals; Antineoplastic Agents, Alkylating; Cell Line, Tumor; Dog Diseases; Dogs; Drug Resistance, Neoplasm; Female; Histiocytic Sarcoma; Imidazoles; Inhibitor of Apoptosis Proteins; Lomustine; Male; Naphthoquinones