Gefitinib (Iressa, ZD1839) inhibits SN38-triggered EGF signals and IL-8 production in gastric cancer cells

• Published in: Cancer chemotherapy and pharmacology Vol. 55; no. 6; pp. 584 - 594
• Main Authors: KISHIDA, Osamu, MIYAZAKI, Yoshiji, SHINOMURA, Yasuhisa, MURAYAMA, Yoko, OGASA, Miyuki, MIYAZAKI, Tamana, YAMAMOTO, Takahiro, WATABE, Kenji, TSUTSUI, Shusaku, KIYOHARA, Tatsuya, SHIMOMURA, Iichiro
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.06.2005; Springer Nature B.V
• Subjects: Amphiregulin; Antineoplastic agents; Antineoplastic Agents - pharmacology; Biological and medical sciences; Camptothecin - analogs & derivatives; Camptothecin - pharmacology; Cell Line, Tumor; Drug Screening Assays, Antitumor; EGF Family of Proteins; Epidermal Growth Factor - metabolism; Gastroenterology. Liver. Pancreas. Abdomen; Glycoproteins - metabolism; Heparin-binding EGF-like Growth Factor; Humans; Intercellular Signaling Peptides and Proteins - metabolism; Interleukin-8 - metabolism; Medical sciences; Pharmacology. Drug treatments; Phosphorylation; Quinazolines - pharmacology; Reactive Oxygen Species - metabolism; Receptor, Epidermal Growth Factor - metabolism; Signal Transduction - drug effects; Stomach Neoplasms - pathology; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Transforming Growth Factor alpha - metabolism; Tumors; Tyrosine - metabolism; Antineoplastic agent; Enzyme; EGF; Transferases; SN38; Cytokine; Enzyme inhibitor; Malignant tumor; IL-8; Stomach cancer; Signal transduction; Signal; Epidermal growth factor; Digestive diseases; EGF receptor; Gefitinib; Protein-tyrosine kinase; Tumor cell; Interleukin 8; Gastric disease
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-004-0959-y

Epidermal growth factor receptor (EGFR) and its ligands are involved in tumor growth, metastasis, angiogenesis, and resistance to chemotherapy. In the experiments described here using AGS gastric cancer cells, SN38 (the active metabolite of CPT-11) induced tyrosine phosphorylation of EGFR within 5 min, and this was followed by the induction of transcripts and/or proteins of heparin-binding EGF-like growth factor, amphiregulin, transforming growth factor-alpha, and interlukin-8 (IL-8). SN38 also activates nuclear factor-kappaB and activator protein-1, both of which are critical for the transcription of the IL-8 gene. However, the blocking of EGFR activation by gefitinib (Iressa, ZD1839), an EGFR-TKI (tyrosine kinase inhibitor), abrogates all the above reactions. The SN38-triggered mechanisms include the generation of reactive oxygen species (ROS) and the activation of protein kinase C (PKC), followed by metalloproteinase activation and the sequential ectodomain shedding of EGFR ligands. These findings suggest that EGF signaling is enhanced by CPT-11 and point to the potential benefit of the use of a combination of CPT-11 with gefitinib in the treatment of certain gastric cancers.