Key Players of Cisplatin Resistance: Towards a Systems Pharmacology Approach

International Journal of Molecular Sciences. 2018;19(3):767 DOI 10.3390/ijms19030767

 

Journal Homepage

Journal Title: International Journal of Molecular Sciences

ISSN: 1661-6596 (Print); 1422-0067 (Online)

Publisher: MDPI AG

LCC Subject Category: Science: Biology (General) | Science: Chemistry

Country of publisher: Switzerland

Language of fulltext: English

Full-text formats available: PDF, HTML, XML

 

AUTHORS

Navin Sarin (Institute of Pharmacy, Clinical Pharmacy, University of Bonn, 53121 Bonn, Germany)
Florian Engel (Federal Institute for Drugs and Medical Devices (BfArM), 53175 Bonn, Germany)
Florian Rothweiler (Institute of Medical Virology, Goethe University Hospital Frankfurt, 60596 Frankfurt/Main, Germany)
Jindrich Cinatl (Institute of Medical Virology, Goethe University Hospital Frankfurt, 60596 Frankfurt/Main, Germany)
Martin Michaelis (Industrial Biotechnology Centre and School of Biosciences, School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK)
Roland Frötschl (Federal Institute for Drugs and Medical Devices (BfArM), 53175 Bonn, Germany)
Holger Fröhlich (Bonn-Aachen International Center for IT (b-it), Life Science Data Analytics & Algorithmic Bioinformatics, University of Bonn, 53115 Bonn, Germany)
Ganna V. Kalayda (Institute of Pharmacy, Clinical Pharmacy, University of Bonn, 53121 Bonn, Germany)

EDITORIAL INFORMATION

Blind peer review

Editorial Board

Instructions for authors

Time From Submission to Publication: 11 weeks

 

Abstract | Full Text

The major obstacle in the clinical use of the antitumor drug cisplatin is inherent and acquired resistance. Typically, cisplatin resistance is not restricted to a single mechanism demanding for a systems pharmacology approach to understand a whole cell’s reaction to the drug. In this study, the cellular transcriptome of untreated and cisplatin-treated A549 non-small cell lung cancer cells and their cisplatin-resistant sub-line A549rCDDP2000 was screened with a whole genome array for relevant gene candidates. By combining statistical methods with available gene annotations and without a previously defined hypothesis HRas, MAPK14 (p38), CCL2, DOK1 and PTK2B were identified as genes possibly relevant for cisplatin resistance. These and related genes were further validated on transcriptome (qRT-PCR) and proteome (Western blot) level to select candidates contributing to resistance. HRas, p38, CCL2, DOK1, PTK2B and JNK3 were integrated into a model of resistance-associated signalling alterations describing differential gene and protein expression between cisplatin-sensitive and -resistant cells in reaction to cisplatin exposure.