title: EGFR blockade by cetuximab alone or as combination therapy for growth control of hepatocellular cancer.
abstract: Hepatocellular carcinoma (HCC) is one of the most common cancer-related causes of death worldwide. In light of the very poor 5 year survival new therapeutic approaches are mandatory. Several reports indicate that the epidermal growth factor receptor (EGFR) is expressed frequently in HCC, most likely contributing to the aggressive growth characteristics of these tumors. Cetuximab, a chimeric monoclonal IgG1 antibody directed against the EGFR, potently suppresses the growth of various cancers but its effect on HCC remains to be explored. We therefore studied the antineoplastic potency of cetuximab in human HCC cells alone and in combination with growth factor tyrosine-kinase inhibition (TKI) or HMG-CoA-reductase inhibiton or conventional cytostatics. Cetuximab inhibited growth of p53 wild-type HepG2 hepatocellular cancer cells in a time- and dose-dependent manner. Cetuximab treatment resulted in arresting the cell cycle in the G(1)/G(0)-phase due to an increase of expression of the cyclin-dependent kinase inhibitors p21(Waf1/CIP1) and p27(Kip1) and a decrease in cyclin D1 expression. Additionally, we observed a moderate increase in apoptosis as demonstrated by caspase-3 activation. Combining cetuximab with TKIs (erlotinib or AG1024) or the HMG-CoA-reductase inhibitor fluvastatin or doxorubicin resulted in synergistic antiproliferative effects. In contrast, p53 mutated Huh-7 hepatocellular cancer cells proved to be less sensitive towards cetuximab, but when combined with TKIs or fluvastatin or doxorubicin a pronounced reduction of cell growth was observed. To conclude, our study may provide a rationale for future clinical investigations of cetuximab combination therapy for growth control of hepatocellular cancer.
authors.affiliation: Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Medical Clinic I, Gastroenterology/Infectious Diseases/Rheumatology, Hindenburgdamm 30, 12200 Berlin, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Huether
authors.forename: Michael
authors.initials: M
authors.lastname: Höpfner
authors.forename: Viola
authors.initials: V
authors.lastname: Baradari
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
authors.forename: Hans
authors.initials: H
authors.lastname: Scherübl
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D000068818:Cetuximab; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D000077340:Fluvastatin; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D011799:Quinazolines / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D011799:Quinazolines; D020032:Tyrphostins; C447031:tyrphostin AG 1024; D000077340:Fluvastatin; D004317:Doxorubicin; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000068818:Cetuximab; D002945:Cisplatin