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Cited by 19Cancer Cells and MetastasisMetal complexes synthesis and propertiesLung Cancer Treatments and Mutations

Generation and Characterisation of Cisplatin-Resistant Non-Small Cell Lung Cancer Cell Lines Displaying a Stem-Like Signature

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Barr, Martin P., Gray, Steven G., Hoffmann, Andreas C., Hilger, Ralf A., Thomale, Juergen, O’Flaherty, John D., Fennell, Dean A., Richard, Derek +2 more·2013·PLoS ONE
DOI 10.1371/journal.pone.0054193PMC PMC3547914
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Abstract

INTRODUCTION: Inherent and acquired cisplatin resistance reduces the effectiveness of this agent in the management of non-small cell lung cancer (NSCLC). Understanding the molecular mechanisms underlying this process may result in the development of novel agents to enhance the sensitivity of cisplatin. METHODS: An isogenic model of cisplatin resistance was generated in a panel of NSCLC cell lines (A549, SKMES-1, MOR, H460). Over a period of twelve months, cisplatin resistant (CisR) cell lines were derived from original, age-matched parent cells (PT) and subsequently characterized. Proliferation (MTT) and clonogenic survival assays (crystal violet) were carried out between PT and CisR cells. Cellular response to cisplatin-induced apoptosis and cell cycle distribution were examined by FACS analysis. A panel of cancer stem cell and pluripotent markers was examined in addition to the EMT proteins, c-Met and β-catenin. Cisplatin-DNA adduct formation, DNA damage (γH2AX) and cellular platinum uptake (ICP-MS) was also assessed. RESULTS: Characterisation studies demonstrated a decreased proliferative capacity of lung tumour cells in response to cisplatin, increased resistance to cisplatin-induced cell death, accumulation of resistant cells in the G0/G1 phase of the cell cycle and enhanced clonogenic survival ability. Moreover, resistant cells displayed a putative stem-like signature with increased expression of CD133+/CD44+cells and increased ALDH activity relative to their corresponding parental cells. The stem cell markers, Nanog, Oct-4 and SOX-2, were significantly upregulated as were the EMT markers, c-Met and β-catenin. While resistant sublines demonstrated decreased uptake of cisplatin in response to treatment, reduced cisplatin-GpG DNA adduct formation and significantly decreased γH2AX foci were observed compared to parental cell lines. CONCLUSION: Our results identified cisplatin resistant subpopulations of NSCLC cells with a putative stem-like signature, providing a further understanding of the cellular events associated with the cisplatin resistance phenotype in lung cancer.

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  • Prior work has assessed the utility of mutational and transcriptomic signatures in predicting response to cisplatin, but none of these advancements have been translated into routine clinical care.

    “Given its widespread use, it comes as no surprise that prior work has assessed the utility of mutational and transcriptomic signatures in predicting response to this drug; yet, to the best knowledge of these authors, none of these advancements have been translated into routine clinical care15–19.”

    From Exploiting convergent phenotypes to derive a pan-cancer cisplatin response gene expression signature (2023) · cites this paper as [15]

    The Introduction says that identifying molecular mechanisms and markers of cisplatin resistance remains important, and the Discussion describes a stem-like signature in resistant NSCLC cell lines. Neither passage addresses studies of mutational or transcriptomic signatures for predicting patient response, or whether such advances have entered routine clinical care. Searches for predictive biomarkers and clinical response found no passage settling those points. (LLM, conf=0.72)

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Authors
Barr, M. P., Gray, S. G., Hoffmann, A. C., Hilger, R. A., Thomale, J., O’Flaherty, J. D., Fennell, D. A., Richard, D., O’Leary, J. J., & O’Byrne, K. J.
Affiliations
  • Trinity College Dublin (IE)
  • Essen University Hospital (DE)
  • University of Leicester (GB)
  • Queensland University of Technology (AU)
Corresponding author
Barr, Martin P.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2013-01-17
Volume
8
Issue
1
Pages
e54193
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0054193
PMC
PMC3547914
OpenAlex
W1889497323
Cited by
19
References
1
Citations by year
2025: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 3 · 2020: 4 · 2019: 2 · 2018: 1 · 2017: 2 · 2016: 2 · 2014: 1
FWCI
0.54
Type
journal article
Language
en
Update notices
correction (2020-05-21)
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • QUT ePrints (Queensland University of Technology) (submittedVersion, cc-by)
  • Arrow@dit (Dublin Institute of Technology) (submittedVersion, cc-by-nc-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • Leicester Research Archive (University of Leicester) (submittedVersion, other-oa)
  • Faculty of Health; Institute of Health and Biomedical Innovation
Funders
Trinity College Dublin
Topics
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Health Sciences › Medicine › Oncology › Metal complexes synthesis and properties
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords
cisplatin resistance, non-small cell lung cancer, cancer stem cells, cell cycle arrest, apoptosis resistance, DNA damage response, cisplatin-DNA adducts, platinum uptake, epithelial-mesenchymal transition, c-Met, β-catenin, ALDH activity, Nanog, Oct4, SOX2, CD133, CD44
MeSH terms
Nanog Homeobox Protein, AC133 Antigen, Aldehyde Dehydrogenase, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Cell Cycle, Cell Survival, Cisplatin, Dose-Response Relationship, Drug, Flow Cytometry, Glycoproteins, Humans, Lung Neoplasms, Peptides, Biomarkers, Tumor, Neoplastic Stem Cells, Antigens, CD, Homeodomain Proteins, DNA Adducts, Hyaluronan Receptors, Drug Resistance, Neoplasm, Proto-Oncogene Proteins c-met, Cell Line, Tumor, Cell Proliferation, Octamer Transcription Factor-3, beta Catenin, SOXB1 Transcription Factors

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