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Int. J. Mol. Sci. 2018, 19(2), 590; https://doi.org/10.3390/ijms19020590

Multifaceted Mechanisms of Cisplatin Resistance in Long-Term Treated Urothelial Carcinoma Cell Lines

1
Department of Urology, Medical Faculty, Heinrich Heine University, 40225 Duesseldorf, Germany
2
Institute of Cell Biology (Cancer Research), University of Duisburg-Essen Medical School, 45122 Essen, Germany
3
Department of Urology, Maastricht University Medical Centre, 6202AZ Maastricht, The Netherlands
4
Department of Obstetrics and Gynaecology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre, 6229HX Maastricht, The Netherlands
*
Author to whom correspondence should be addressed.
Received: 12 January 2018 / Revised: 9 February 2018 / Accepted: 13 February 2018 / Published: 16 February 2018
(This article belongs to the Special Issue Platinum-Based Anti-Tumor Drugs)
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Abstract

Therapeutic efficacy of cisplatin-based treatment of late stage urothelial carcinoma (UC) is limited by chemoresistance. To elucidate underlying mechanisms and to develop new approaches for overcoming resistance, we generated long-term cisplatin treated (LTT) UC cell lines, characterised their cisplatin response, and determined the expression of molecules involved in cisplatin transport and detoxification, DNA repair, and apoptosis. Inhibitors of metallothioneins and Survivin were applied to investigate their ability to sensitise towards cisplatin. Cell growth, proliferation, and clonogenicity were examined after cisplatin treatment by MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, EdU (5-ethynyl-2’-deoxyuridine) incorporation assay, and Giemsa staining, respectively. Cell cycle distribution and apoptosis were quantified by flow cytometry. mRNA and protein expressions were measured by real-time quantitative (qRT)-PCR, western blot, or immunofluorescence staining. LTTs recovered rapidly from cisplatin stress compared to parental cells. In LTTs, to various extents, cisplatin exporters and metallothioneins were induced, cisplatin adduct levels and DNA damage were decreased, whereas expression of DNA repair factors and specific anti-apoptotic factors was elevated. Pharmacological inhibition of Survivin, but not of metallothioneins, sensitised LTTs to cisplatin, in an additive manner. LTTs minimise cisplatin-induced DNA damage and evade apoptosis by increased expression of anti-apoptotic factors. The observed diversity among the four LTTs highlights the complexity of cisplatin resistance mechanisms even within one tumour entity, explaining heterogeneity in patient responses to chemotherapy. View Full-Text
Keywords: urothelial carcinoma; cisplatin; resistance mechanisms; metallothionein; Survivin; YM155 urothelial carcinoma; cisplatin; resistance mechanisms; metallothionein; Survivin; YM155
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Skowron, M.A.; Melnikova, M.; van Roermund, J.G.H.; Romano, A.; Albers, P.; Thomale, J.; Schulz, W.A.; Niegisch, G.; Hoffmann, M.J. Multifaceted Mechanisms of Cisplatin Resistance in Long-Term Treated Urothelial Carcinoma Cell Lines. Int. J. Mol. Sci. 2018, 19, 590.

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