Abstract
Hepatocellular carcinoma (HCC) overexpresses insulin-like growth factor-I receptor (IGF-IR), as compared with normal hepatocytes. Since IGF-1R-mediated signaling promotes survival, oncogenic transformation and tumor growth and spread, it represents a potential target for treating HCC. Here, we have generated a murine anti-IGF-1R antibody, 4F2, that recognizes the IGF-IRα subunit and blocks in vitro IGF-I and IGF-II-induced cell proliferation of SMMC-7721 and Bel-7402 HCC cell lines. 4F2 can inhibit IGF-IR autophosphorylation, IRS-1 phosphorylation and the activation of the major downstream signaling molecules AKT and mitogen-activated protein kinase. Additionally, we observed a moderate increase in apoptosis as demonstrated by detection of changes in the expression of the pro-apoptotic and anti-apoptotic proteins Bax and Bcl-2 after 4F2 treatment. Combined treatment with 4F2 and doxorubicin was more effective in reducing cell proliferation and promoting apoptosis than either agent alone. These data support that therapeutic anti-IGF-IR antibodies are potential new agents for treating HCC.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / administration & dosage
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Antibodies, Monoclonal / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Apoptosis / drug effects
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Carcinoma, Hepatocellular / drug therapy*
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology
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Cell Line, Tumor / drug effects
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Cell Proliferation / drug effects
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Doxorubicin / administration & dosage
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Doxorubicin / pharmacology
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Drug Screening Assays, Antitumor / methods
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Gene Expression Regulation, Neoplastic
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Humans
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Insulin-Like Growth Factor I / pharmacology
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Insulin-Like Growth Factor II / pharmacology
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Liver Neoplasms / drug therapy*
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology
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Mice
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Mice, Inbred BALB C
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Receptor, IGF Type 1 / genetics
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Receptor, IGF Type 1 / immunology*
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Signal Transduction / drug effects
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bcl-2-Associated X Protein / metabolism
Substances
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Antibodies, Monoclonal
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BAX protein, human
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Proto-Oncogene Proteins c-bcl-2
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bcl-2-Associated X Protein
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Insulin-Like Growth Factor I
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Insulin-Like Growth Factor II
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Doxorubicin
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Receptor, IGF Type 1