Selective growth inhibition by suppression of F1Fo ATPase in canine malignant melanoma cell lines.
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 IC50compared 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.
Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan.
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S
Kuroki
Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan.
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Kobayashi
Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan.
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Tani
Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan.
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Miyamoto
Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan.
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Kurita
Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan.
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Tamura
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.
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Ono
Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan.
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Washizu
Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan.
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Bonkobara
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004283:Dog Diseases / Q000188:drug therapy*; D004285:Dogs; D004354:Drug Screening Assays, Antitumor / Q000662:veterinary; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D061985:Madin Darby Canine Kidney Cells / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy / Q000662:veterinary*; D009840:Oligomycins / Q000627:therapeutic use*; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009840:Oligomycins; D006180:Proton-Translocating ATPases