Abstract
Expression of legumain, a novel asparaginyl endopeptidase, in tumors was identified from gene expression profiling and tumor tissue array analysis. Legumain was demonstrated in membrane-associated vesicles concentrated at the invadopodia of tumor cells and on cell surfaces where it colocalized with integrins. Legumain was demonstrated to activate progelatinase A. Cells overexpressing legumain possessed increased migratory and invasive activity in vitro and adopted an invasive and metastatic phenotype in vivo, inferring significance of legumain in tumor invasion and metastasis. A prodrug strategy incorporating a legumain-cleavable peptide substrate onto doxorubicin was developed. The prototype compound, designated legubicin, exhibited reduced toxicity and was effectively tumoricidal in vivo in a murine colon carcinoma model.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antibiotics, Antineoplastic / pharmacokinetics*
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Biotransformation
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Colonic Neoplasms / drug therapy
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Colonic Neoplasms / enzymology*
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Colonic Neoplasms / genetics
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Colonic Neoplasms / pathology
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Cysteine Endopeptidases / biosynthesis*
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Cysteine Endopeptidases / genetics
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Doxorubicin / analogs & derivatives*
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Doxorubicin / pharmacokinetics
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Enzyme Activation
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Enzyme Precursors / metabolism
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Gelatinases / metabolism
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Gene Expression Profiling
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Humans
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Leucine / pharmacokinetics
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Metalloendopeptidases / metabolism
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Mice
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Mice, Inbred BALB C
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Neoplasm Invasiveness
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Neoplasm Metastasis
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Plant Proteins / biosynthesis*
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Plant Proteins / genetics
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Prodrugs / pharmacokinetics*
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
Substances
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Antibiotics, Antineoplastic
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Enzyme Precursors
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Plant Proteins
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Prodrugs
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RNA, Messenger
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Doxorubicin
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Cysteine Endopeptidases
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asparaginylendopeptidase
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Gelatinases
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Metalloendopeptidases
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progelatinase
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Leucine