DNA-bound platinum is the major determinant of cisplatin sensitivity in head and neck squamous carcinoma cells

• Published in: PloS one 2013-04, Vol.8 (4), p.e61555
• Main Authors: Martens-de Kemp, Sanne R, Dalm, Simone U, Wijnolts, Fiona M J, Brink, Arjen, Honeywell, Richard J, Peters, Godefridus J, Braakhuis, Boudewijn J M, Brakenhoff, Ruud H
• Format: Article
• Language: English
• Subjects: Accumulation; Adducts; Anemia; Apoptosis; Biology; BRCA1 protein; BRCA2 protein; Breast cancer; Cancer therapies; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Care and treatment; Cell cycle; Cell Line, Tumor; Cell Proliferation - drug effects; Chemotherapy; Cisplatin; Cisplatin - metabolism; Cisplatin - pharmacology; Cisplatin - therapeutic use; Correlation; Deoxyribonucleic acid; DNA; DNA adducts; DNA Adducts - metabolism; DNA Adducts - pharmacology; DNA damage; DNA repair; DNA, Neoplasm - metabolism; Drug Screening Assays, Antitumor; Efflux; ERCC1 protein; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genes; Genes, Neoplasm - genetics; Head & neck cancer; Head and neck cancer; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - pathology; Humans; Inhibitory Concentration 50; Medical research; Medicine; Mutation; Mutation - genetics; Oct-4 protein; Otolaryngology; p53 Protein; Parameter sensitivity; Platinum; Platinum - pharmacology; Platinum - therapeutic use; Radiation therapy; Radiotherapy; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sensitivity; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck; Statistics, Nonparametric; Surgery; Tumor proteins; Tumor Suppressor Protein p53 - genetics; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0061555

The combination of systemic cisplatin with local and regional radiotherapy as primary treatment of head and neck squamous cell carcinoma (HNSCC) leads to cure in approximately half of the patients. The addition of cisplatin has significant effects on outcome, but despite extensive research the mechanism underlying cisplatin response is still not well understood. We examined 19 HNSCC cell lines with variable cisplatin sensitivity. We determined the TP53 mutational status of each cell line and investigated the expression levels of 11 potentially relevant genes by quantitative real-time PCR. In addition, we measured cisplatin accumulation and retention, as well as the level of platinum-DNA adducts. We found that the IC50 value was significantly correlated with the platinum-DNA adduct levels that accumulated during four hours of cisplatin incubation (p = 0.002). We could not find a significant correlation between cisplatin sensitivity and any of the other parameters tested, including the expression levels of established cisplatin influx and efflux transporters. Furthermore, adduct accumulation did not correlate with mRNA expression of the investigated influx pumps (CTR1 and OCT3) nor with that of the examined DNA repair genes (ATR, ATM, BRCA1, BRCA2 and ERCC1). Our findings suggest that the cisplatin-DNA adduct level is the most important determinant of cisplatin sensitivity in HNSCC cells. Imaging with radio-labeled cisplatin might have major associations with outcome.