Minodronate, a newly developed nitrogen-containing bisphosphonate, suppresses melanoma growth and improves survival in nude mice by blocking vascular endothelial growth factor signaling

Sho Ichi Yamagishi, Riichiro Abe, Yosuke Inagaki, Kazuo Nakamura, Hiroshi Sugawara, Daisuke Inokuma, Hideki Nakamura, Tadamichi Shimizu, Masayoshi Takeuchi, Akihiko Yoshimura, Richard Bucala, Hiroshi Shimizu, Tsutomu Imaizumi

Research output: Contribution to journalArticle

76 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1865-1874
Number of pages10
JournalAmerican Journal of Pathology
Volume165
Issue number6
Publication statusPublished - 2004 Dec
Externally publishedYes

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Diphosphonates
Nude Mice
Vascular Endothelial Growth Factor A
Melanoma
Nitrogen
Endothelial Cells
Growth
Cell Death
Neoplasms
Chemokine CCL2
NADPH Oxidase
Angiogenesis Inducing Agents
DNA
Intercellular Adhesion Molecule-1
Mitogens
Blood Vessels
YM 529
Cultured Cells
Reactive Oxygen Species
Macrophages

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Minodronate, a newly developed nitrogen-containing bisphosphonate, suppresses melanoma growth and improves survival in nude mice by blocking vascular endothelial growth factor signaling. / Yamagishi, Sho Ichi; Abe, Riichiro; Inagaki, Yosuke; Nakamura, Kazuo; Sugawara, Hiroshi; Inokuma, Daisuke; Nakamura, Hideki; Shimizu, Tadamichi; Takeuchi, Masayoshi; Yoshimura, Akihiko; Bucala, Richard; Shimizu, Hiroshi; Imaizumi, Tsutomu.

In: American Journal of Pathology, Vol. 165, No. 6, 12.2004, p. 1865-1874.

Research output: Contribution to journalArticle

Yamagishi, SI, Abe, R, Inagaki, Y, Nakamura, K, Sugawara, H, Inokuma, D, Nakamura, H, Shimizu, T, Takeuchi, M, Yoshimura, A, Bucala, R, Shimizu, H & Imaizumi, T 2004, 'Minodronate, a newly developed nitrogen-containing bisphosphonate, suppresses melanoma growth and improves survival in nude mice by blocking vascular endothelial growth factor signaling', American Journal of Pathology, vol. 165, no. 6, pp. 1865-1874.
Yamagishi, Sho Ichi ; Abe, Riichiro ; Inagaki, Yosuke ; Nakamura, Kazuo ; Sugawara, Hiroshi ; Inokuma, Daisuke ; Nakamura, Hideki ; Shimizu, Tadamichi ; Takeuchi, Masayoshi ; Yoshimura, Akihiko ; Bucala, Richard ; Shimizu, Hiroshi ; Imaizumi, Tsutomu. / Minodronate, a newly developed nitrogen-containing bisphosphonate, suppresses melanoma growth and improves survival in nude mice by blocking vascular endothelial growth factor signaling. In: American Journal of Pathology. 2004 ; Vol. 165, No. 6. pp. 1865-1874.
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