Cisplatin resistance induced in germ cell tumour cells is due to reduced susceptibility towards cell death but not to altered DNA damage induction or repair

Fenske, Annabelle Elisabeth; Glaesener, Stephanie; Bokemeyer, Carsten; Thomale, Jüergen; Dahm-Daphi, Jochen; Honecker, Friedemann; Dartsch, Dorothee C.

doi:10.1016/j.canlet.2012.05.009

Cited by 18 publications

(24 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In agreement with previous results, 7,8,36 no changes in cell viability, apoptosis or cell cycle progression were detected immediately after cisplatin treatment, and therefore they were measured 24 h after the end of the treatment. Intracellular Pt content, cisplatin G-G intra-strand crosslinks, and DNA strand breaks were determined immediately after treatment (AT-0 time) and also one hour later (AT-1 time).…”

Section: Discussionsupporting

confidence: 91%

“…46,47 On the other hand, the lack of differences in cisplatin adducts between AT-0 and AT-1 times not only for the A2780 cells but also for the A549 and A2780cis cells (all repair active cells), demonstrated that there is an equilibrium between adducts being repaired/removed and new adducts being formed by the remaining intracellular cisplatin, at least in the 1 h time lapse studied, as suggested before. 48 Besides, the repair/removal of cisplatininduced DNA adducts in these cells seemed to be a relatively slow process, as described for A2780 23 and the other cells; 8,23,49 however, it is important to address that no adducts were detected 24 h after the end of treatment (data not shown).…”

Section: Discussionmentioning

confidence: 87%

“…For the A2780 cells at lower doses, and for the A549 and A2780cis cells at all cisplatin concentrations, the results revealed cell cycle arrests at the G2/M-phase, as described before for cisplatin treatments, 18 even after low dose exposure. 8 Considering that low levels of XPA protein were specifically related to cisplatin sensitivity 40 and to increased cell apoptosis, 41 the highest sensitivity of the GM04312 cells was most likely due to the lack of XPA protein. 7 This possibility was supported by the increases in adduct levels detected in these cells at AT-1 time, compared to AT-0 time, demonstrating the absence of DNA adduct repair.…”

Section: Discussionmentioning

confidence: 99%

“…of Functional Biology (Genetic Area) and Oncology University Institute and inter-and intra-strand crosslinks. [4][5][6] The most frequently generated cisplatin-induced adducts, intra-strand guanineguanine (G-G) cross-links, can block DNA replication and transcription [6][7][8] and lead to cell cycle arrest and apoptosis. 6 Tumors can become resistant to cisplatin by a variety of processes, such as decreased uptake/influx or increased efflux of the drug; low apoptosis capacity due to hypermethylation of gene promoters; increased DNA repair activity and/or increased DNA adduct bypass activity.…”

Section: Introductionmentioning

confidence: 99%

“…[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. 17 Furthermore, cisplatin can also induce genomic instability, which is generally measured as the presence of DNA strand breaks.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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

et al. 2017

View full text Add to dashboard Cite

Cisplatin, one of the most extensively used metallodrugs in cancer treatment, presents the important drawback of patient resistance. This resistance is the consequence of different processes including those preventing the formation of DNA adducts and/or their quick removal. Thus, a tool for the accurate detection and quantitation of cisplatin-induced adducts might be valuable for predicting patient resistance. To prove the validity of such an assumption, highly sensitive plasma mass spectrometry (ICP-MS) strategies were applied to determine DNA adduct levels and intracellular Pt concentrations. These two metal-relative parameters were combined with an evaluation of biological responses in terms of genomic stability (with the Comet assay) and cell cycle progression (by flow cytometry) in four human cell lines of different origins and cisplatin sensitivities (A549, GM04312, A2780 and A2780cis), treated with low cisplatin doses (5, 10 and 20 mM for 3 hours). Cell viability and apoptosis were determined as resistance indicators. Univariate linear regression analyses indicated that quantitation of cisplatin-induced G-G intra-strand adducts, measured 1 h after treatment, was the best predictor for viability and apoptosis in all of the cell lines. Multivariate linear regression analyses revealed that the prediction improved when the intracellular Pt content or the Comet data were included in the analysis, for all sensitive cell lines and for the A2780 and A2780cis cell lines, respectively. Thus, a reliable cisplatin resistance predictive model, which combines the quantitation of adducts by HPLC-ICP-MS, and their repair, with the intracellular Pt content and induced genomic instability, might be essential to identify early therapy failure. Significance to metallomicsKnowledge about cisplatin as a chemotherapy drug is extensive, including information about the several processes that contribute to its resistance, the main problem of using this chemical. However, this knowledge and information does not yet allow the early identification of resistant tumors/patients, one of the most desired aims of clinicians. In this work we have developed a model that might allow the early detection of chemical resistance and, more importantly, might do so mostly regardless of the resistance mechanism involved, because it determines the dynamics of adduct induction/repair, considering chemical influx/efflux and induced genomic instability.

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2017

View full text Add to dashboard Cite

show abstract

Proteomic profiling of cisplatin-resistant and cisplatin-sensitive germ cell tumour cell lines using quantitative mass spectrometry

et al. 2022

View full text Add to dashboard Cite

Purpose Advanced testicular germ cell tumours (GCT) generally have a good prognosis owing to their unique sensitivity towards cisplatin-based chemotherapies. However, cisplatin-resistant GCT have a poor outcome. Further studies are mandatory to better understand resistance mechanisms and develop therapeutic strategies for refractory GCTs. Methods Protein levels in cisplatin-resistant GCT cell lines of NTERA-2, NCCIT and 2102EP were analyzed by quantitative proteomic mass spectrometry (MS) in combination with stable isotope labelling by amino acids in cell culture (SILAC). Differentially abundant protein markers of acquired cisplatin resistance were validated by Western blotting. Comprehensive bioinformatical annotation using gene set enrichment analyses (GSEA) and STRING interaction analysis were performed to identify commonly affected pathways in cisplatin resistance and the data were compared to the GCT cohort of the ‘The Cancer Genome Atlas’. Results A total of 4375 proteins were quantified by MS, 144 of which were found to be differentially abundant between isogenic resistant and sensitive cell line pairs (24 proteins for NTERA-2, 60 proteins for NCCIT, 75 proteins for 2102EP). Western blotting confirmed regulation of key resistance-associated proteins (CBS, ANXA1, LDHA, CTH, FDXR). GSEA revealed a statistically significant enrichment of DNA repair-associated proteins in all three resistant cell lines and specific additional processes for individual cell lines. Conclusion High resolution MS combined with SILAC is a powerful tool and 144 significantly deregulated proteins were found in cisplatin-resistant GCT cell lines. Our study provides the largest proteomic in vitro library for cisplatin resistance in GCT, yet, enabling further studies to develop new treatment options for patients with refractory GCT.

show abstract

Cabazitaxel overcomes cisplatin resistance in germ cell tumour cells

Gerwing

Jacobsen

Dyshlovoy

et al. 2016

J Cancer Res Clin Oncol

View full text Add to dashboard Cite

show abstract

Cisplatin resistance induced in germ cell tumour cells is due to reduced susceptibility towards cell death but not to altered DNA damage induction or repair

Cited by 18 publications

References 62 publications

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

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

Proteomic profiling of cisplatin-resistant and cisplatin-sensitive germ cell tumour cell lines using quantitative mass spectrometry

Cabazitaxel overcomes cisplatin resistance in germ cell tumour cells

Contact Info

Product

Resources

About