Document Detail


Inhibition of the EGF receptor blocks autocrine growth and increases the cytotoxic effects of doxorubicin in rat hepatoma cells: role of reactive oxygen species production and glutathione depletion.
MedLine Citation:
PMID:  18371937     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
FaO rat hepatoma cells show increased levels of the epidermal growth factor receptor (EGFR) ligands, when compared with adult normal hepatocytes, and higher activity of the TNF-alpha converting enzyme (TACE/ADAM17), which is required for EGFR ligand proteolysis and activation. In this work we have analysed the consequences of inhibiting the EGFR in FaO rat hepatoma cells, focusing the attention on autocrine growth and protection from apoptosis. Results have indicated that FaO cells show overactivation of the EGFR pathway, which induces basal growth (in the absence of serum) and protection from pro-apoptotic agents, such as doxorubicin, generating drug resistance. Treatment of cells with the combination of doxorubicin and the tyrphostin 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478, a potent and specific inhibitor of EGFR tyrosine kinase) potently inhibits autocrine growth and induces apoptosis. The apoptotic effect correlates with high expression and activation of the pro-apoptotic Bax and decreased transcript and protein levels of the anti-apoptotic Mcl-1 and Bcl-x(L). Furthermore, the combination of AG1478 and doxorubicin induces reactive oxygen species (ROS) production and glutathione depletion in FaO cells, coincident with up-regulation of the NADPH oxidase NOX4 and down-regulation of the gamma-glutamylcysteine synthetase (gamma-GCS), a key regulatory enzyme of the glutathione synthesis. Incubation of cells with glutathione ethyl ester attenuates the apoptosis induced by the combination of doxorubicin and AG1478, which indicates that glutathione depletion is required for an efficient cell death. In conclusion, targeting EGFR combined with other conventional pro-apoptotic drugs should potentially be effective in antineoplastic therapy towards liver cancer.
Authors:
Conrad Ortiz; Laia Caja; Patricia Sancho; Esther Bertran; Isabel Fabregat
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-02-19
Journal Detail:
Title:  Biochemical pharmacology     Volume:  75     ISSN:  1873-2968     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2008 May 
Date Detail:
Created Date:  2008-04-28     Completed Date:  2008-05-16     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1935-45     Citation Subset:  IM    
Affiliation:
Fundació Institut d'Investigació Biomèdica de Bellvitge, Centre d'Oncologia Molecular, Gran Via s/n, Km 2.7, 08907 L'Hospitalet, Barcelona, Spain.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antibiotics, Antineoplastic / pharmacology*
Apoptosis / drug effects
Caspase 3 / metabolism
Cell Cycle / drug effects
Cell Line, Tumor
Cells, Cultured
Doxorubicin / pharmacology*
Glutathione / metabolism
Hepatocytes / drug effects,  metabolism
Male
Protein Tyrosine Phosphatases / pharmacology*
Rats
Rats, Wistar
Reactive Oxygen Species / metabolism
Receptor, Epidermal Growth Factor / antagonists & inhibitors*
Tyrphostins / pharmacology*
bcl-2-Associated X Protein / metabolism
Chemical
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/Bax protein, rat; 0/Egfr protein, rat; 0/Reactive Oxygen Species; 0/Tyrphostins; 0/bcl-2-Associated X Protein; 170449-18-0/tyrphostin AG 1478; 23214-92-8/Doxorubicin; 70-18-8/Glutathione; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 3.1.3.48/Protein Tyrosine Phosphatases; EC 3.4.22.-/Caspase 3

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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