Cisplatin resistance of the HNSCC cell line UT-SCC-26A can be overcome by stimulation of the EGF-receptor.
The epidermal growth factor receptor (EGFR, ErbB1, HER1) is frequently overexpressed in head and neck squamous cell carcinomas (HNSCCs) and correlates with disease progression and reduced survival of the patient. The aim of this study was to investigate the influence of EGFR stimulation on cisplatin sensitivity in 3 previously well characterized HNSCC cell lines. The HNSCC cell lines UMB-SCC-745, -864 and UT-SCC-26A were incubated for 13 h in the presence of 0.1, 1, 10, 100 or 1000 ng/mL EGF. Cell cycle checkpoint distribution was determined by FACS analysis. Effects of cisplatin on cell viability were evaluated with the MTT assay. UT-SCC-26A cells were resistant to the highest cisplatin concentrations (100 microM). However, during treatment with rising EGF levels UT-SCC-26A tumor cells became susceptible to cisplatin. Cell cycle analysis revealed a very low level of UT-SCC-26A cells in G(2)/M phase that rose after stimulation with EGF. Also, after EGFR stimulation, cyclin D1 and CHK2 levels increased most prominently in UT-SCC-26A, whereas CHK2 levels dropped again at higher EGF concentrations. Overall, cellular proliferation and cisplatin IC(50) exhibited inverse behaviour. Taken together the data suggest that EGFR stimulation in some cases could be an important prerequisite for cisplatin sensitivity. Therefore, future studies should investigate potential opposing effects of such combination therapies that consist of cell proliferation inhibitors in conjunction with cisplatin treatment. In addition, studies should also include investigations regarding possible therapeutic benefits of tumor cell proliferation-activating agents, that could render resistant HNSCC tumor cells sensitive to chemotherapy treatment.
Mandic
Robert
R
Department of Otorhinolaryngology, University Hospital Giessen and Marburg, Campus Marburg, Deutschhausstrasse 3, D-35037 Marburg, Germany. mandic@med.uni-marburg.de
Rodgarkia-Dara
Chantal J
CJ
Krohn
Vanessa
V
Wiegand
Susanne
S
Grénman
Reidar
R
Werner
Jochen A
JA
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D002945:Cisplatin