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PLoS One. 2017 Jul 26;12(7):e0181081. doi: 10.1371/journal.pone.0181081. eCollection 2017.

Cisplatin resistance in non-small cell lung cancer cells is associated with an abrogation of cisplatin-induced G2/M cell cycle arrest.

Author information

1
Institute of Pharmacy, Clinical Pharmacy, University of Bonn, Bonn, Germany.
2
Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany.
3
Institute of Medical Virology, Goethe University Hospital Frankfurt, Frankfurt/Main, Germany.
4
Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury United Kingdom.
5
Institute of Pharmacy, Clinical Pharmacy, University of Greifswald, Greifswald, Germany.

Abstract

The efficacy of cisplatin-based chemotherapy in cancer is limited by the occurrence of innate and acquired drug resistance. In order to better understand the mechanisms underlying acquired cisplatin resistance, we have compared the adenocarcinoma-derived non-small cell lung cancer (NSCLC) cell line A549 and its cisplatin-resistant sub-line A549rCDDP2000 with regard to cisplatin resistance mechanisms including cellular platinum accumulation, DNA-adduct formation, cell cycle alterations, apoptosis induction and activation of key players of DNA damage response. In A549rCDDP2000 cells, a cisplatin-induced G2/M cell cycle arrest was lacking and apoptosis was reduced compared to A549 cells, although equitoxic cisplatin concentrations resulted in comparable platinum-DNA adduct levels. These differences were accompanied by changes in the expression of proteins involved in DNA damage response. In A549 cells, cisplatin exposure led to a significantly higher expression of genes coding for proteins mediating G2/M arrest and apoptosis (mouse double minute 2 homolog (MDM2), xeroderma pigmentosum complementation group C (XPC), stress inducible protein (SIP) and p21) compared to resistant cells. This was underlined by significantly higher protein levels of phosphorylated Ataxia telangiectasia mutated (pAtm) and p53 in A549 cells compared to their respective untreated control. The results were compiled in a preliminary model of resistance-associated signaling alterations. In conclusion, these findings suggest that acquired resistance of NSCLC cells against cisplatin is the consequence of altered signaling leading to reduced G2/M cell cycle arrest and apoptosis.

PMID:
28746345
PMCID:
PMC5528889
DOI:
10.1371/journal.pone.0181081
[Indexed for MEDLINE]
Free PMC Article

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