Unknown

Dataset Information

0

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


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.

SUBMITTER: Skowron MA 

PROVIDER: S-EPMC5855812 | biostudies-other | 2018 Feb

REPOSITORIES: biostudies-other

altmetric image

Publications

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

Skowron Margaretha A MA   Melnikova Margarita M   van Roermund Joep G H JGH   Romano Andrea A   Albers Peter P   Thomale Juergen J   Schulz Wolfgang A WA   Niegisch Günter G   Hoffmann Michèle J MJ  

International journal of molecular sciences 20180216 2


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 inv  ...[more]

Similar Datasets

| S-EPMC6785536 | biostudies-literature
| S-EPMC5578070 | biostudies-literature
| S-EPMC5173062 | biostudies-literature
| S-EPMC9604399 | biostudies-literature
| S-EPMC4660687 | biostudies-literature
| S-EPMC6539474 | biostudies-literature
| S-EPMC9102668 | biostudies-literature
| S-EPMC7541007 | biostudies-literature
| S-EPMC9421311 | biostudies-literature
| S-EPMC6129731 | biostudies-literature