Cancer Chemotherapy and Pharmacology

, Volume 55, Issue 4, pp 393–403 | Cite as

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

  • Osamu Kishida
  • Yoshiji Miyazaki
  • Yoko Murayama
  • Miyuki Ogasa
  • Tamana Miyazaki
  • Takahiro Yamamoto
  • Kenji Watabe
  • Shusaku Tsutsui
  • Tatsuya Kiyohara
  • Iichiro Shimomura
  • Yasuhisa Shinomura
Original Article
First Online:
Received:
Accepted:

Abstract

The epidermal growth factor receptor (EGFR) and its ligands are involved in tumor growth, metastasis, angiogenesis, and resistance to chemotherapy. The findings reported here demonstrate that SN38 (the active metabolite of CPT-11) induces the tyrosine phosphorylation of EGFR within 5 min, followed by the induction of transcripts and/or proteins of the heparin-binding EGF-like growth factor, amphiregulin, transforming growth factor-α, and interlukin-8 (IL-8) in AGS gastric cancer cells. SN38 also activates nuclear factor-κB 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.

Keywords

Gefitinib Epidermal growth factor Epidermal growth factor receptor SN38 Interleukin-8 

Abbreviation

AP-1

Activator protein-1

AR

Amphiregulin

CPT

Camptothecin

EGF

Epidermal growth factor

EGFR

EGF receptor

ELISA

Enzyme-linked immunosorbent assay

EMSA

Electrophoretic mobility shift assay

GAPDH

Glyceraldehyde 3-phosphate dehydrogenase

HB-EGF

Heparin-binding EGF-like growth factor

IL-8

Interleukin-8

NAC

N-Acetylcysteine

NF-κB

Nuclear factor-kappaB

ROS

Reactive oxygen species

TGF

Transforming growth factor

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Notes

Acknowledgements

This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Osamu Kishida
    • 1
  • Yoshiji Miyazaki
    • 1
  • Yoko Murayama
    • 1
  • Miyuki Ogasa
    • 1
  • Tamana Miyazaki
    • 1
  • Takahiro Yamamoto
    • 1
  • Kenji Watabe
    • 1
  • Shusaku Tsutsui
    • 1
  • Tatsuya Kiyohara
    • 1
  • Iichiro Shimomura
    • 1
  • Yasuhisa Shinomura
    • 1
  1. 1.Department of Internal Medicine and Molecular Science, Graduate School of MedicineOsaka UniversityOsakaJapan

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