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

International Journal of Molecular Sciences
Margaretha A SkowronMichèle J Hoffmann

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 facto...Continue Reading

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Citations

Oct 31, 2020·Scientific Reports·Sabrina BorchertFabian D Mairinger
Mar 7, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Lena BerningBjörn Stork
Mar 23, 2021·Scientific Reports·Miguel Angel Merlos RodrigoVojtech Adam
Jul 29, 2021·Cancer Letters·Margaretha A SkowronDaniel Nettersheim

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Methods Mentioned

BETA
FCS
PCR
Fluorescence

Software Mentioned

CompuSyn
ACAS
Focinator
MACSQuant Analyzer

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis