title: Antitumor effects of CRM197, a specific inhibitor of HB-EGF, in T-cell acute lymphoblastic leukemia.
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.
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Kunami
authors.forename: Fusanori
authors.initials: F
authors.lastname: Yotsumoto
authors.forename: Kenji
authors.initials: K
authors.lastname: Ishitsuka
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Fukami
authors.forename: Takashi
authors.initials: T
authors.lastname: Odawara
authors.forename: Sadao
authors.initials: S
authors.lastname: Manabe
authors.forename: Toyokazu
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tamura
authors.forename: Masahide
authors.initials: M
authors.lastname: Kuroki
authors.forename: Shingo
authors.initials: S
authors.lastname: Miyamoto
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001426:Bacterial Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D004167:Diphtheria Toxin / Q000008:administration & dosage / Q000494:pharmacology*; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D066246:ErbB Receptors / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018773:Genes, erbB-1; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D019169:Jurkat Cells / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D001426:Bacterial Proteins; D004167:Diphtheria Toxin; D006131:Growth Inhibitors; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D047428:Protein Kinase Inhibitors; C028581:CRM197 (non-toxic variant of diphtheria toxin); D004317:Doxorubicin; C512478:EGFR protein, human; D066246:ErbB Receptors