title: Minodronate, a newly developed nitrogen-containing bisphosphonate, suppresses melanoma growth and improves survival in nude mice by blocking vascular endothelial growth factor signaling.
abstract: Angiogenesis, a process by which new vascular networks are formed from pre-existing capillaries, is required for tumors to grow, invade, and metastasize. Vascular endothelial growth factor (VEGF), a specific mitogen to endothelial cells, is a crucial factor for tumor angiogenesis. In this study, we investigated whether minodronate, a newly developed nitrogen-containing bisphosphonate, could inhibit melanoma growth and improve survival in nude mice by suppressing the VEGF signaling. We found here that minodronate inhibited melanoma growth and improved survival in nude mice by suppressing the tumor-associated angiogenesis and macrophage infiltration. Minodronate completely inhibited the VEGF-induced increase in DNA synthesis and tube formation in endothelial cells by suppressing NADPH oxidase-mediated reactive oxygen species generation and Ras activation. Furthermore, minodronate inhibited the VEGF-induced expression of intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 in endothelial cells. Minodronate decreased DNA synthesis and increased apoptotic cell death of cultured melanoma cells as well. Our present study suggests that minodronate might suppress melanoma growth and improve survival in nude mice by two independent mechanisms; one is by blocking the VEGF signaling in endothelial cells, and the other is by inducing apoptotic cell death of melanoma. The present study provides a novel potential therapeutic strategy for the treatment of melanoma.
authors.affiliation: Department of Internal Medicine III, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan. shoichi@med.kurume-u.ac.jp
authors.forename: Sho-ichi
authors.initials: S
authors.lastname: Yamagishi
authors.forename: Riichiro
authors.initials: R
authors.lastname: Abe
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Inagaki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nakamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sugawara
authors.forename: Daisuke
authors.initials: D
authors.lastname: Inokuma
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakamura
authors.forename: Tadamichi
authors.initials: T
authors.lastname: Shimizu
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimizu
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Imaizumi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002448:Cell Adhesion / Q000187:drug effects; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004164:Diphosphonates / Q000627:therapeutic use*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D008546:Melanoma, Experimental / Q000098:blood supply / Q000401:mortality / Q000517:prevention & control*; D051379:Mice; D008819:Mice, Nude; D019255:NADPH Oxidases / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012878:Skin Neoplasms / Q000098:blood supply / Q000401:mortality / Q000517:prevention & control*; D015996:Survival Rate; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; C087958:YM 529; D004247:DNA; D019255:NADPH Oxidases; D020830:rac1 GTP-Binding Protein