Kuroki S, Kobayashi M, Tani H, Miyamoto R, Kurita S, Tamura K, Ono K, Washizu T, Bonkobara M
Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan.
Japan Animal Referral Medical Center, Takatsu-ku, Kawasaki-shi, Kanagawa, Japan.
J Vet Pharmacol Ther. 2017 Jan;40(1):101-104. doi: 10.1111/jvp.12336. Epub 2016 Jun 13.
Canine malignant melanoma (CMM) is a highly aggressive and fatal neoplasm. To identify potential therapeutic compounds and/or targets, 320 compounds were screened for their growth inhibitory activity in a CMM line (CMM-1) using a chemical library known to target specific signaling pathways/cell growth-related molecules. Among the compounds screened, the F1Fo ATPase inhibitor oligomycin showed potent growth inhibitory effects in CMM-1 cells, while exhibiting less toxic effects in a non-neoplastic control cell line (MDCK cells). The growth inhibitory effect of oligomycin A was then examined using six CMM lines and MDCK cells. Three CMM lines were highly sensitive to oligomycin A, with around 3000-20 000 times lower IC compared with oligomycin A-resistant CMM lines and MDCK cells. Oligomycin A-sensitive CMM-1 cells exhibited much greater oligomycin A-induced decreases in cellular ATP compared to oligomycin A-resistant cell lines. Although the oligomycins are clinically unsuitable because of its in vivo toxicity, these findings implicate the potential of F1Fo ATPase as a therapeutic target in a subset of CMM.
犬恶性黑色素瘤（CMM）是一种极具侵袭性和致命性的肿瘤。为了确定潜在的治疗化合物和/或靶点，使用一个已知可靶向特定信号通路/细胞生长相关分子的化学文库，对320种化合物在一种CMM细胞系（CMM-1）中的生长抑制活性进行了筛选。在筛选的化合物中，F1Fo ATP酶抑制剂寡霉素在CMM-1细胞中显示出强大的生长抑制作用，而在非肿瘤对照细胞系（MDCK细胞）中表现出较低的毒性作用。然后使用六种CMM细胞系和MDCK细胞检测了寡霉素A的生长抑制作用。三种CMM细胞系对寡霉素A高度敏感，与对寡霉素A耐药的CMM细胞系和MDCK细胞相比，其半数抑制浓度（IC）低约3000 - 20000倍。与对寡霉素A耐药的细胞系相比，对寡霉素A敏感的CMM-1细胞在寡霉素A诱导下细胞ATP的降低幅度要大得多。尽管由于寡霉素的体内毒性，其在临床上不适用，但这些发现暗示了F1Fo ATP酶作为一部分CMM治疗靶点的潜力。
