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Int. J. Mol. Sci. 2018, 19(3), 767; https://doi.org/10.3390/ijms19030767

Key Players of Cisplatin Resistance: Towards a Systems Pharmacology Approach

1
Institute of Pharmacy, Clinical Pharmacy, University of Bonn, 53121 Bonn, Germany
2
Federal Institute for Drugs and Medical Devices (BfArM), 53175 Bonn, Germany
3
Institute of Medical Virology, Goethe University Hospital Frankfurt, 60596 Frankfurt/Main, Germany
4
Industrial Biotechnology Centre and School of Biosciences, School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK
5
Bonn-Aachen International Center for IT (b-it), Life Science Data Analytics & Algorithmic Bioinformatics, University of Bonn, 53115 Bonn, Germany
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 7 February 2018 / Revised: 27 February 2018 / Accepted: 27 February 2018 / Published: 7 March 2018
(This article belongs to the Special Issue Platinum-Based Anti-Tumor Drugs)
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Abstract

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. View Full-Text
Keywords: cisplatin resistance; cellular signalling; HRas; p38; CCL2; DOK1; PTK2B; JNK3 cisplatin resistance; cellular signalling; HRas; p38; CCL2; DOK1; PTK2B; JNK3
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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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Sarin, N.; Engel, F.; Rothweiler, F.; Cinatl, J.; Michaelis, M.; Frötschl, R.; Fröhlich, H.; Kalayda, G.V. Key Players of Cisplatin Resistance: Towards a Systems Pharmacology Approach. Int. J. Mol. Sci. 2018, 19, 767.

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