gms | German Medical Science

128. Kongress der Deutschen Gesellschaft für Chirurgie

Deutsche Gesellschaft für Chirurgie

03.05. - 06.05.2011, München

Inhibition of the epidermal growth factor receptor reverses ATP-binding cassette protein mediated multi-drug resistance in hepatocellular carcinoma

Meeting Abstract

  • Katrin Hoffmann - Ruprechts Karls Universität Heidelberg, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Heidelberg
  • Zhi Xiao - Ruprechts Karls Universität Heidelberg, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Heidelberg
  • Clemens Franz - Ruprechts Karls Universität Heidelberg, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Heidelberg
  • Elvira Mohr - Ruprechts Karls Universität Heidelberg, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Heidelberg
  • Daniel Schultze - Ruprechts Karls Universität Heidelberg, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Heidelberg
  • Susanne Serba - Ruprechts Karls Universität Heidelberg, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Heidelberg
  • Markus W. Büchler - Universitätsklinikum Heidelberg, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Heidelberg
  • Peter Schemmer - Ruprechts Karls Universität Heidelberg, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Heidelberg

Deutsche Gesellschaft für Chirurgie. 128. Kongress der Deutschen Gesellschaft für Chirurgie. München, 03.-06.05.2011. Düsseldorf: German Medical Science GMS Publishing House; 2011. Doc11dgch349

DOI: 10.3205/11dgch349, URN: urn:nbn:de:0183-11dgch3496

Veröffentlicht: 20. Mai 2011

© 2011 Hoffmann et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielfältigt, verbreitet und öffentlich zugänglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

Introduction: Signalling through the epidermal growth factor receptor (EGFR) activated tyrosine kinase cascade and over-expression of multi-drug resistance mediating ATP-binding cassette proteins (ABC transport proteins) play an important role in the development of hepatocellular carcinoma (HCC). Recent evidence suggests an involvement of the EGFR in the regulation of multi-drug resistance in cancer cells. The aim of this study was to systematically explore the effect of EGFR-inhibition in multi-drug resistant HCC cells that overexpress ABC transport proteins.

Materials and methods: Drug resistant HepG2 and HuH7 cells were developed by escalating concentrations of chemotherapeutic agents in the culture media. The effects of EGFR inhibition were investigated by MTT-assay, rhodamine up-take assay, quantitative RT-PCR and western blot.

Results: Treatment with gemcitabine or doxorubicin induces multi-drug resistance and significantly increases the ABC-transport protein expression and function in a time- and dose-dependent manner. Additionally, conventional chemotherapy increased the mRNA expression of tyrosine kinases by up to 50% and enhanced the phosphorylation of ERK. Activation of the tyrosine kinase pathway by EGF increased the multi-drug resistance, up-regulated the ABC-transporter mRNA expression up to 3-fold and enhanced the survival of resistant HCC cells. Consistent with these effects, inhibition of the EGFR using siRNA decreased the ABC transporter protein mRNA expression by up to 56% and inhibited the proliferation of resistant cells. Gefitinib, a clinically approved EGFR inhibitor, restored the chemosensitivity of resistant HCC cells. Simultaneous treatment with Gefitinib caused a dose-dependent reversal of resistance to conventional chemotherapy in HepG2 and HuH7 cells by reducing the mRNA expression and inhibiting the efflux function of ABC transport proteins.

Conclusion: These data provide fort he first time evidence that the multi-drug resistance of HCC is modulated through the EGFR-activated tyrosine kinase cascade. Consequentially, the restoration of chemosensitivity by EGFR inhibition can lead towards new tailored therapies in patients with highly resistant tumors.