Abstract
The therapeutic outcome for T-cell acute lymphoblastic leukemia (T-ALL) remains poor; thus, novel, targeted therapies are urgently needed. Recently, we showed that heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the EGF family, is a promising target for the treatment of various types of cancer. The aim of the present study was to investigate whether HB-EGF is a therapeutic target for T-ALL, and to further elucidate the antitumor effects of a specific inhibitor of HB-EGF, cross-reacting material 197 (CRM197). We elucidated the expression of HB-EGF in T-ALL cell lines, and evaluated the effect of CRM197 on these cells alone or in combination with anticancer agent. The expression of EGFR and EGFR ligands was determined by flow cytometry, RT-PCR and real-time quantitative PCR. Induction of apoptosis was assessed by TUNEL assay. HB-EGF was strongly expressed by T-ALL cell lines, and the expression of both HB-EGF and EGFR was enhanced by doxorubicin. CRM197 induced apoptosis, and furthermore, the combination of CRM197 plus doxorubicin enhanced cytotoxicity in a T-ALL cell line. These results suggest that HB-EGF is a promising therapeutic target for T-ALL.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents, Phytogenic / administration & dosage
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Antineoplastic Agents, Phytogenic / pharmacology
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Apoptosis / drug effects
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Bacterial Proteins / administration & dosage
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Bacterial Proteins / pharmacology*
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Breast Neoplasms / pathology
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Cell Line, Tumor / drug effects
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Cell Line, Tumor / metabolism
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Diphtheria Toxin / administration & dosage
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Diphtheria Toxin / pharmacology*
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Doxorubicin / administration & dosage
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Doxorubicin / pharmacology
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Drug Screening Assays, Antitumor
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Drug Synergism
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ErbB Receptors / biosynthesis
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Gene Expression Regulation, Neoplastic / drug effects
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Genes, erbB-1
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Growth Inhibitors / administration & dosage
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Growth Inhibitors / pharmacology*
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Heparin-binding EGF-like Growth Factor
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Humans
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Intercellular Signaling Peptides and Proteins / biosynthesis*
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Jurkat Cells / drug effects
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Jurkat Cells / metabolism
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Ligands
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology*
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / pharmacology*
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Signal Transduction / drug effects
Substances
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Antineoplastic Agents
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Antineoplastic Agents, Phytogenic
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Bacterial Proteins
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Diphtheria Toxin
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Growth Inhibitors
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HBEGF protein, human
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Heparin-binding EGF-like Growth Factor
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Intercellular Signaling Peptides and Proteins
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Ligands
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Protein Kinase Inhibitors
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CRM197 (non-toxic variant of diphtheria toxin)
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Doxorubicin
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EGFR protein, human
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ErbB Receptors