DNA-Bound Platinum Is the Major Determinant of Cisplatin Sensitivity in Head and Neck Squamous Carcinoma Cells

Abstract

PurposeThe 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.MethodsWe 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.ResultsWe 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).ConclusionOur 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.

Detection of Increased 64Cu Uptake by Human Copper Transporter 1 Gene Overexpression Using PET with 64CuCl2 in Human Breast Cancer Xenograft Model

“…However, Holzer et al reported that an enhanced expression of hCTR1 in ovarian cancer cells induced higher accumulation of CDDP and copper but only a marginal increase in the cytotoxicity of CDDP due to improper intracellular localization of CDDP (14). Therefore, the cytotoxicity induced by CTR1 expression and CDDP in cancer cells might still be controversial (28)(29)(30), and this issue should be resolved by performing a further study.…”

Cisplatin resistance in cell models: evaluation of metallomic and biological predictive biomarkers to address early therapy failure

“…Furthermore, differences in intracellular cisplatin at AT-0 and AT-1 times revealed a considerable cisplatin efflux after one hour for all the cell lines except A2780cis, which was much higher and faster than those reported before. 14,23,37,48 In the analysis of genomic stability, the Comet assay is the most widely used tool. 34 However, detection of DNA strand breaks after cisplatin treatment is not a straightforward result; some authors reported them in different cells and organisms, 20,26 and others reported their absence.…”

“…2,7,9,10 Since most of these processes are ultimately associated with the prevention of cisplatin-DNA adduct formation, or with their fast removal from the exposed DNA, the accurate detection and quantitation of DNA adducts may be a valuable tool in the early prediction of resistance. [11][12][13][14][15] However, there are some inconsistencies in the literature regarding the value of the cisplatin-DNA adduct level per se as a resistance predictive factor. 8,12 It has been known for several years that cisplatin treatment is able to modify cell cycle progression, [16][17][18] and that this modification could be different for sensitive and resistant cells.…”

Defects in the Fanconi Anemia Pathway and Chromatid Cohesion in Head and Neck Cancer

“…Sporadic and Fanconi anemia HNSCC cell lines were established as described previously (19)(20)(21). All three FA-HNSCC cell lines were genetically corrected.…”