RESUMEN
Canine lymphoma is the most common cancer in dogs and has a poor prognosis. We recently found that the endocytosis inhibitor dynasore suppresses the viability of human cancer cell lines, especially hematopoietic cancers, by inducing apoptosis. In the present study, we examined the anticancer effects of dynasore on five previously established canine lymphoma cell lines (CLBL-1, Ema, Nody-1, CLC, and GL-1). Dynasore suppressed cell viability in these canine lymphoma cell lines more effectively than in human cancer cell lines. It also induced apoptosis in CLBL-1 and Ema cells but not in peripheral blood mononuclear cells in healthy dogs or in Madin-Darby canine kidney (MDCK) cells, suggesting that the ability of dynasore to induce apoptosis is cancer-specific. Furthermore, dynasore induced a DNA damage response in CLBL-1 and Ema cells, suggesting that it acts as a genotoxic agent in canine lymphoma cell lines. These findings suggest that endocytosis inhibitors may provide a new anticancer treatment for canine lymphoma.
Asunto(s)
Enfermedades de los Perros , Linfoma , Animales , Perros , Humanos , Leucocitos Mononucleares/metabolismo , Línea Celular Tumoral , Linfoma/tratamiento farmacológico , Linfoma/veterinaria , Linfoma/genética , Apoptosis , Endocitosis , Enfermedades de los Perros/genéticaRESUMEN
Endocytosis has been shown to play an important role in cancer proliferation and metastasis. Recent studies have accumulated evidence that endocytosis inhibitors suppress in vitro and in vivo proliferation and migration. In addition, endocytosis inhibition has been shown to induce apoptosis, but its mechanism remains largely unclear. In this study, we found that the endocytosis inhibitor dynasore causes a cell viability reduction in multiple cancer cell lines, especially in hematopoietic cancers. Dynasore induced massive apoptosis and an S-phase progression delay. In addition, dynasore activated the ATR-Chk1 DNA damage response, which suggests a single-stranded DNA exposure induced by DNA replication stress. Furthermore, an ATR inhibitor sensitized the dynasore-induced apoptosis. These findings suggest that endocytosis inhibitors may have an ability to suppress DNA replication, a common mechanism of genotoxic chemotherapies targeting cancer, and that the anti-cancer effects of endocytosis inhibitors may be sensitized by DNA damage response inhibitors.