title: Involvement of the epidermal growth factor receptor in the modulation of multidrug resistance in human hepatocellular carcinoma cells in vitro.
abstract: BACKGROUND
  Hepatocellular carcinoma (HCC) is a molecular complex tumor with high intrinsic drug resistance. Recent evidence suggests an involvement of the tyrosine kinase pathway in the regulation of ATP-binding cassette protein (ABC-transport protein) mediated multidrug resistance in cancer cells. The aim of this study was to examine whether EGFR inhibition sensitizes HCCs to chemotherapy and to elucidate its mechanism.
  
  
  RESULTS
  Chemotherapeutic treatment induces multidrug resistance and significantly increases ABC-transport protein expression and function in a time- and dose-dependent manner in HCC cells. Furthermore, cytostatic treatment increases the mRNA expression of tyrosine kinases and induces the phosphorylation of ERK. EGF activation of the tyrosine kinase pathway up-regulated the ABC-transport protein mRNA expression and enhanced the survival of resistant HCC cells. Consistent with these effects, inhibition of the EGFR using siRNA decreased the ABC-transport protein mRNA expression and inhibited the proliferation of resistant cells. Additional treatment with Gefitinib, a clinically approved EGFR inhibitor, caused a dose-dependent reversal of resistance to conventional chemotherapy.
  
  
  CONCLUSIONS
  The present study demonstrates that the multidrug resistance of HCC is modulated through the EGF-activated tyrosine kinase cascade. Consequentially, the restoration of chemosensitivity by EGFR inhibition may lead towards new tailored therapies in patients with highly resistant tumors.
authors.affiliation: Department of General and Transplantation Surgery, Ruprecht-Karls-University, Heidelberg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Hoffmann
authors.affiliation: Department of General and Transplantation Surgery, Ruprecht-Karls-University, Heidelberg, Germany.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: Department of General and Transplantation Surgery, Ruprecht-Karls-University, Heidelberg, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Franz
authors.affiliation: Department of General and Transplantation Surgery, Ruprecht-Karls-University, Heidelberg, Germany.
authors.forename: Elvira
authors.initials: E
authors.lastname: Mohr
authors.affiliation: Department of General and Transplantation Surgery, Ruprecht-Karls-University, Heidelberg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Serba
authors.affiliation: Department of General and Transplantation Surgery, Ruprecht-Karls-University, Heidelberg, Germany.
authors.forename: Markus W
authors.initials: MW
authors.lastname: Büchler
authors.affiliation: Department of General and Transplantation Surgery, Ruprecht-Karls-University, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schemmer
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