Key Players of Cisplatin Resistance: Towards a Systems Pharmacology Approach.
Navin Sarin, Florian Engel, Florian Rothweiler, Jindrich Cinatl, Martin Michaelis, Roland Frötschl, Holger Fröhlich, Ganna V Kalayda
Author Information
Navin Sarin: Institute of Pharmacy, Clinical Pharmacy, University of Bonn, 53121 Bonn, Germany. n.sarin@uni-bonn.de.
Florian Engel: Federal Institute for Drugs and Medical Devices (BfArM), 53175 Bonn, Germany. engel_florian@hotmail.de.
Florian Rothweiler: Institute of Medical Virology, Goethe University Hospital Frankfurt, 60596 Frankfurt/Main, Germany. f.rothweiler@kinderkrebsstiftung-frankfurt.de.
Jindrich Cinatl: Institute of Medical Virology, Goethe University Hospital Frankfurt, 60596 Frankfurt/Main, Germany. cinatl@em.uni-frankfurt.de.
Martin Michaelis: Industrial Biotechnology Centre and School of Biosciences, School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK. M.Michaelis@kent.ac.uk.
Roland Frötschl: Federal Institute for Drugs and Medical Devices (BfArM), 53175 Bonn, Germany. Roland.Froetschl@bfarm.de. ORCID
Holger Fröhlich: Bonn-Aachen International Center for IT (b-it), Life Science Data Analytics & Algorithmic Bioinformatics, University of Bonn, 53115 Bonn, Germany. frohlich@bit.uni-bonn.de. ORCID
Ganna V Kalayda: Institute of Pharmacy, Clinical Pharmacy, University of Bonn, 53121 Bonn, Germany. akalayda@uni-bonn.de. ORCID
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 A549CDDP 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 (p38) and 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.
