Key Players of Cisplatin Resistance: Towards a Systems Pharmacology Approach

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...

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Bibliographic Details
Published in:International journal of molecular sciences 2018-03, Vol.19 (3), p.767
Main Authors: Sarin, Navin, Engel, Florian, Rothweiler, Florian, Cinatl, Jindrich, Michaelis, Martin, Frötschl, Roland, Fröhlich, Holger, Kalayda, Ganna V
Format: Article
Language:English
Subjects:
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Antineoplastic Agents - pharmacology
Biomarkers
Cell Line, Tumor
Chemotherapy
Cisplatin
Cisplatin - pharmacology
Computational Biology - methods
Dok1 protein
Drug Resistance, Neoplasm - drug effects
Drug Resistance, Neoplasm - genetics
Gene expression
Gene Ontology
Genes
Genomes
Genomics - methods
Humans
JNK3 protein
Lung cancer
Monocyte chemoattractant protein 1
Non-small cell lung carcinoma
Pharmacogenetics - methods
Pharmacology
Proteins
Proteomes
Signal Transduction
Statistical methods
Systems Biology - methods
Workflow
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Summary: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 A549 CDDP 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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms19030767