Abstract
Tumor-associated macrophages (TAM) play a critical role in promoting tumor development and metastasis. In the present study, we found that legumain, an asparaginyl endopeptidase, was highly expressed on the surface of TAM. A doxorubicin-based prodrug specifically activated by legumain selectively ablated TAM and resulted in a significant reduction of angiogenic factors and related tumor vessel growth. Treatment with the prodrug also suppressed circulating tumor cells and myeloid immune suppressor Gr-1+/CD11b+ cells in tumor-bearing animals. After selective ablation of TAM using the prodrug, tumor growth and metastases were greatly inhibited in murine tumor models. These results indicate that legumain-activated prodrugs targeting TAM in tumors might represent a novel anticancer strategy.
© 2013 Japanese Cancer Association.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Cysteine Endopeptidases / biosynthesis
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Cysteine Endopeptidases / genetics
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Cysteine Endopeptidases / metabolism
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Disease Progression
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Doxorubicin / analogs & derivatives
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Doxorubicin / pharmacology
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Female
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Humans
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Macrophages / enzymology
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Macrophages / metabolism
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Macrophages / pathology*
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Male
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Mice
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Mice, Inbred BALB C
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Myeloid Cells / drug effects
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Myeloid Cells / metabolism
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Myeloid Cells / pathology
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Neoplasm Metastasis
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Neoplasms / blood supply*
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Neoplasms / drug therapy
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Neoplasms / metabolism
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Neoplasms / pathology*
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Neovascularization, Pathologic / drug therapy
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Neovascularization, Pathologic / genetics
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Neovascularization, Pathologic / metabolism
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Neovascularization, Pathologic / pathology*
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Oligopeptides / pharmacology
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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LEG-3 prodrug
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Oligopeptides
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Doxorubicin
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Cysteine Endopeptidases
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asparaginylendopeptidase