HB-EGF inhibition in combination with various anticancer agents enhances its antitumor effects in gastric cancer.
Advanced gastric cancer (GC) is one of the most lethal malignancies. Although many anticancer agents exist for the treatment of GC, its prognosis remains extremely poor. Therefore, further development of targeted therapies is required for patients with GC. To assess the role of heparin-binding epidermal growth factor-like growth factor (HB-EGF) as a target for GC therapy, the expression of EGF receptor ligands in GC cell lines, and the antitumor effects of an HB-EGF inhibitor (CRM197) as a single agent and in combination with other anticancer agents was assessed in GC cells. HB-EGF was the predominantly expressed ligand among EGF receptor ligands in all the cells. CRM197 induced significant cell apoptosis. Anticancer agents augmented the secretion of HB-EGF into the medium and simultaneously induced cell apoptosis. Combination of CRM197 with other anticancer agents significantly enhanced cell apoptosis. Additionally, co-administration of CRM197 and paclitaxel resulted in synergistic antitumor effects. These results suggested that HB-EGF is a rational target for GC therapy.
Sanui
Ayako
A
Department of Obstetrics and Gynecology, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
Yotsumoto
Fusanori
F
Tsujioka
Hiroshi
H
Fukami
Tatsuya
T
Horiuchi
Shinji
S
Shirota
Kyoko
K
Yoshizato
Toshiyuki
T
Kawarabayashi
Tatsuhiko
T
Kuroki
Masahide
M
Miyamoto
Shingo
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003470:Culture Media; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D017239:Paclitaxel / Q000494:pharmacology; D034741:RNA, Small Interfering; D013274:Stomach Neoplasms / Q000473:pathology*
D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D003470:Culture Media; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; C028581:CRM197 (non-toxic variant of diphtheria toxin); D066246:ErbB Receptors; D017239:Paclitaxel