title: The proteasome inhibitor bortezomib inhibits the growth of canine malignant melanoma cells in vitro and in vivo.
abstract: Canine malignant melanomas are highly aggressive and fatal neoplasms. In the present report, 21 drugs that target specific signalling pathways were screened for their growth inhibitory activity on three canine malignant melanoma cell lines. The proteasome inhibitor bortezomib inhibited the growth of these cell lines. The growth inhibitory properties of bortezomib were then examined using nine canine malignant melanoma cell lines. Bortezomib demonstrated potent growth inhibitory activity in all cell lines with calculated IC50 values of 3.5-5.6 nM. Because suppression of the NF-κB pathway by preventing proteasomic degradation of I κB is an important mechanism of the anti-tumour activity of bortezomib, the activation status of and the effect of bortezomib on the NF-κB pathway were examined using a canine malignant melanoma cell line, CMM-1. The NF-κB pathway was constitutively activated in CMM-1 cells and bortezomib efficiently suppressed this activated pathway. Using a CMM-1 xenograft mouse model, bortezomib also significantly inhibited tumour growth via suppression of tumour cell proliferation. Collectively, these findings suggest that bortezomib has growth inhibitory activity against canine malignant melanomas potentially through suppression of the constitutively activated NF-κB pathway. Targeted therapy using bortezomib could therefore be beneficial in the management of canine malignant melanomas.
authors.affiliation: Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, 1-7-1 Kyonan-cho, Musashino-shi, Tokyo 180-8602, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Ito
authors.forename: Masato
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Shiori
authors.initials: S
authors.lastname: Kuroki
authors.forename: Yu
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Taisuke
authors.initials: T
authors.lastname: Iwata
authors.forename: Kohei
authors.initials: K
authors.lastname: Mori
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kuroki
authors.forename: Yuta
authors.initials: Y
authors.lastname: Ozawa
authors.forename: Masanori
authors.initials: M
authors.lastname: Tetsuka
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Teruyo
authors.initials: T
authors.lastname: Hiroi
authors.forename: Hitomi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Ono
authors.forename: Tsukimi
authors.initials: T
authors.lastname: Washizu
authors.forename: Makoto
authors.initials: M
authors.lastname: Bonkobara
mesh_terms: D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004283:Dog Diseases / Q000188:drug therapy* / Q000209:etiology; D004285:Dogs; D008545:Melanoma / Q000188:drug therapy / Q000209:etiology / Q000662:veterinary*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D012878:Skin Neoplasms; D000096142:Cutaneous Malignant Melanoma
chemical_list: D001897:Boronic Acids; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib
keywords: Bortezomib; Dog; Melanoma; NF-κB