Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Abbreviations

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

References

  1. Pommier Y, Pourquier P, Fan Y, Strumberg D (1998) Mechanism of action of eukaryotic DNA topoisomerase I and drugs targeted to the enzyme. Biochim Biophys Acta 1400:83–105

    Article  CAS  PubMed  Google Scholar 

  2. Kunimoto T, Nitta K, Tanaka T, Uehara N, Baba H, Takeuchi M, Yokokura T, Sawada S, Miyasaka T, Mutai M (1987) Antitumor activity of 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy-camptothecin, a novel water-soluble derivative of camptothecin, against murine tumors. Cancer Res 47:5944–5947

    CAS  PubMed  Google Scholar 

  3. Bleiberg H (1999) CPT-11 in gastrointestinal cancer. Eur J Cancer 35:371–379

    Article  CAS  PubMed  Google Scholar 

  4. Ajani JA, Baker J, Pisters PW, Ho L, Mansfield PF, Feig BW, Charnsangavej C (2001) CPT-11 plus cisplatin in patients with advanced, untreated gastric or gastroesophagus junction carcinoma. Cancer 94:641–646

    Article  Google Scholar 

  5. Motwani M, Sirotnak FM, She Y, Commes T, Schwartz K (2002) Drg1, a novel target for modulating sensitivity to CPT-11 in colon cancer cells. Cancer Res 62:3950–3955

    CAS  PubMed  Google Scholar 

  6. Hiraoka W, Vazquez N, Nieves-Neira W, Chanock SJ, Pommier Y (1998) Role of oxygen radicals generated by NADPH oxidase in apoptosis induced in human leukemia cells. J Clin Invest 102:1961–1968

    CAS  PubMed  Google Scholar 

  7. Miyazaki Y, Hiraoka S, Tsutsui S, Kitamura S, Shinomura Y, Matsuzawa Y (2001) Epidermal growth factor receptor mediates stress-induced expression of its ligands in rat gastric epithelial cells. Gastroenterology 120:108–116

    CAS  PubMed  Google Scholar 

  8. Huang RP, Peng A, Golard A, Hossain MZ, Huang R, Liu YG, Boynton AL (2001) Hydrogen peroxide promotes transformation of rat liver non-neoplastic epithelial cells through activation of epidermal growth factor receptor. Mol Carcinog 30:209–217

    Article  CAS  PubMed  Google Scholar 

  9. Borrell-Pages M, Rojo F, Albanell J, Baselga J, Arribas J (2003) TACE is required for activation of the EGFR by TGF-α in tumors. EMBO J 22:1114–1124

    Article  CAS  PubMed  Google Scholar 

  10. Hirata A, Ogawa S, Kometani T, Kuwano T, Naito S, Kuwano M, Ono M (2002) ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase. Cancer Res 62:2554–2560

    CAS  PubMed  Google Scholar 

  11. Ciadiello F, Tortora G (2001) A novel approach in the treatment of cancer: targeting the epidermal growth factor receptor. Clin Cancer Res 7:2958–2970

    PubMed  Google Scholar 

  12. Mendelsohn J, Baselga J (2000) The EGF receptor family as targets for cancer therapy. Oncogene 19:6550–6565

    Article  CAS  PubMed  Google Scholar 

  13. Ciardiello F, Caputo R, Bianco R, Damiano V, Fontanini G, Cuccato S, Placido S, De Bianco AR, Tortora G (2001) Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res 7:1459–1465

    CAS  PubMed  Google Scholar 

  14. Huang SM, Li J, Armstrong EA, Harari PM (2002) Modulation of radiation response and tumor-induced angiogenesis after epidermal growth factor receptor inhibition by ZD1839 (Iressa). Cancer Res 62:4300–4306

    CAS  PubMed  Google Scholar 

  15. Raben D, Helfrich BA, Chan D, Johnson G, Bunn PA Jr (2002) ZD1839, a selective epidermal growth factor receptor tyrosine kinase inhibitor, alone and in combination with radiation and chemotherapy as a new therapeutic strategy in non-small cell lung cancer. Semin Oncol 29:37–46

    Article  CAS  PubMed  Google Scholar 

  16. Douglass EC (2003) Development of ZD1839 in colorectal cancer. Semin Oncol 30:17–22

    Article  CAS  Google Scholar 

  17. Hiraoka S, Miyazaki Y, Kitamura S, Toyota M, Kiyohara T, Shinomura Y, Mukaida N, Matsuzawa Y (2001) Gastrin induces CXC chemokine expression in gastric epithelial cells through activation of NF-κB. Am J Physiol Gastrointest Liver Physiol 281:G735–G742

    CAS  PubMed  Google Scholar 

  18. Digman JD, Lebovit RM, Roeder RG (1983) Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res 11:1475–1489

    PubMed  Google Scholar 

  19. Noguchi H, Sakamoto C, Wada K, Akamatsu T, Uchida T, Tatsuguchi A, Matsui H, Fukui H, Fujimori T, Kasuga M (1999) Expression of Heregulin α, erbB2, and erbB3 and their influences on proliferation of gastric epithelial cells. Gastroenterology 117:1119–1127

    CAS  PubMed  Google Scholar 

  20. Normanno N, Bianco C, De Luca A, Maiello MR, Salomon DS (2003) Target-based agents against ErbB receptors and their ligands: a novel approach to cancer treatment. Endocr Relat Cancer 10:1–21

    CAS  PubMed  Google Scholar 

  21. Simizu S, Takada M, Umezawa K, Imoto M (1998) Requirement of caspase-3(-like) protease-mediated hydrogen peroxide production for apoptosis induced by various anticancer drugs. J Biol Chem 273:26900–26907

    Article  CAS  PubMed  Google Scholar 

  22. Lemjabbar H, Li D, Gallup M, Sidhu S, Drori E, Basbaum C (2003) Tobacco smoke-induced lung cell proliferation mediated by tumor necrosis factor alpha-converting enzyme and amphiregulin. J Biol Chem 278:26202–26207

    Article  CAS  PubMed  Google Scholar 

  23. Takenobu H, Yamazaki A, Hirata M, Umata T, Mekada E (2003) The stress- and inflammatory cytokine-induced ectodomain shedding of heparin-binding epidermal growth factor-like growth factor is mediated by p38 MAPK, distinct from the 12-O-tetradecanoylphorbol-13-acetate- and lysophosphatidic acid-induced signaling cascades. J Biol Chem 278:17255–17262

    Article  CAS  PubMed  Google Scholar 

  24. Prenzel N, Zwick E, Daub H, Leserer M, Abraham R, Wallasch C, Ullrich A (1999) EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature 402:884–888

    CAS  PubMed  Google Scholar 

  25. Barnard JA, Graves-Deal R, Pittelkow MR, Dubois RN, Cook P, Ramsey GW, Bishop PR, Damstrup L, Coffey RJ (1994) Auto- and cross-induction within the mammalian epidermal growth factor-related polypeptide family. J Biol Chem 269:22817–22822

    CAS  PubMed  Google Scholar 

  26. Huang S, Mills L, Mian B, Tellez C, McCarty M, Yang X-D, Gudas JM, Bar-Eli M (2002) Fully humanized neutralizing antibodies to interleukin-8 (ABX-IL-8) inhibit angiogenesis, tumor growth, and metastasis of human melanoma. Am J Pathol 161:125–134

    CAS  PubMed  Google Scholar 

  27. Mukaida N, Mahe Y, Matsushima K (1990) Cooperative interaction of nuclear factor-κB- and cis-regulatory enhancer binding protein-like factor binding elements in activating the interleukin-8 gene by pro-inflammatory cytokines. J Biol Chem 265:21128–21133

    CAS  PubMed  Google Scholar 

  28. Naef M, Yokoyama M, Friess H, Buchler MW, Korc M (1996) Co-expression of heparin-binding EGF-like growth factor and related peptides in human gastric carcinoma. Int J Cancer 66:315–321

    Article  CAS  PubMed  Google Scholar 

  29. Ravid T, Sweeney C, Gee P, Carraway KL III, Goldkorn T (2002) Epidermal growth factor receptor activation under oxidative stress fails to promote c-Cbl mediated down-regulation. J Biol Chem 277:31214–31219

    Article  CAS  PubMed  Google Scholar 

  30. Konishi H, Tanaka M, Takemura Y, Matsuzaki H, Ono Y, Kikkawa U, Nishizuka Y (1997) Activation of protein kinase C by tyrosine phosphorylation in response to H2O2. Proc Natl Acad Sci U S A 94:11233–11237

    Article  CAS  PubMed  Google Scholar 

  31. Sun X, Wu F, Datta R, Kharbanda S, Kufe D (2000) Interaction between protein kinase C delta and the c-Abl tyrosine kinase in the cellular response to oxidative stress. J Biol Chem 275:7470–7473

    Article  CAS  PubMed  Google Scholar 

  32. Majumder PK, Mishra NC, Sun X, Bharti A, Kharbanda S, Saxena S, Kufe D (2001) Targeting of protein kinase C delta to mitochondria in the oxidative stress response. Cell Growth Differ 12:465–470

    CAS  PubMed  Google Scholar 

  33. Cesaro P, Raiteri E, Demoz M, Castino R, Baccino FM, Bonelli G, Isidoro C (2001) Expression of protein kinase C beta1 confers resistance to TNF alpha- and paclitaxel-induced apoptosis in HT-29 colon carcinoma cells. Int J Cancer 93:179–184

    Article  CAS  PubMed  Google Scholar 

  34. Han Y, Han ZY, Zhou XM, Shi R, Zheng Y, Shi YQ, Miao JY, Pan BR, Fan DM (2002) Expression and function of classical protein kinase C isoenzymes in gastric cancer cell line and its drug-resistant sublines. World J Gastroenterol 8:441–445

    CAS  PubMed  Google Scholar 

  35. Kitadai Y, Haruma K, Mukaida N, Ohmoto Y, Matsutani N, Yasui W, Yamamoto S, Sumii K, Kajiyama G, Fidler IJ, Tahara E (2000) Regulation of disease-progression genes in human gastric carcinoma cells by Interleukin 8. Clin Cancer Res 6:2735–2740

    CAS  PubMed  Google Scholar 

  36. Bottero V, Busuttil V, Loubat A, Magnè N, Fischel J-L, Milano G, Peyron J-F (2001) Activation of nuclear factor κB through the IKK complex by the topoisomerase poisons SN38 and doxorubicin: a brake to apoptosis in HeLa human carcinoma cells. Cancer Res 61:7785–7791

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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

Author information

Authors and Affiliations

  1. Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Osamu Kishida, Yoshiji Miyazaki, Yoko Murayama, Miyuki Ogasa, Tamana Miyazaki, Takahiro Yamamoto, Kenji Watabe, Shusaku Tsutsui, Tatsuya Kiyohara, Iichiro Shimomura & Yasuhisa Shinomura

Authors
  1. Osamu Kishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yoshiji Miyazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yoko Murayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Miyuki Ogasa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tamana Miyazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takahiro Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kenji Watabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shusaku Tsutsui
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tatsuya Kiyohara
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Iichiro Shimomura
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yasuhisa Shinomura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Osamu Kishida.

Additional information

“Iressa” is a trademark of the AstraZeneca group of companies.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kishida, O., Miyazaki, Y., Murayama, Y. et al. Gefitinib (“Iressa”, ZD1839) inhibits SN38-triggered EGF signals and IL-8 production in gastric cancer cells. Cancer Chemother Pharmacol 55, 393–403 (2005). https://doi.org/10.1007/s00280-004-0904-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-004-0904-0

Keywords

Search

Navigation