Resistance to platinum-based chemotherapy in lung cancer cell lines

Our plain-English summary of Resistance to platinum-based chemotherapy in lung cancer cell lines, by J. Chen, N. Emara, C. Solomides, et al (Cancer Chemotherapy and Pharmacology, 2010).

The study

• Authors: J. Chen, N. Emara, C. Solomides, H. Parekh, H. Simpkins
• Journal: Cancer Chemotherapy and Pharmacology
• Published: 2010;66(6):1103-11
• Cited by: 28 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose: A series of six lung cancer cell lines of different cell origin (including small cell and mesothelioma) were characterized immunohistochemically and the role of a series of protein candidates previously implicated in drug resistance were investigated.

Methods: These include colony-forming and cell growth assays, immunohistochemistry, siRNA knockouts, real-time PCR and western blots.

Results: No correlation was found with AKT, HO-1, HO-2, GRP78, 14-3-3zeta and ERCC1 levels and cisplatin nor oxaliplatin cytotoxicity, but an association was observed with levels of the enzyme, dihydrodiol dehydrogenase (DDH); an enzyme previously implicated in the development of platinum resistance. The relationship appeared to hold true for those cell lines derived from lung epithelial primary tumors but not for the neuroendocrine/small-cell and mesothelioma cell lines. siRNA knockouts to DDH-1 and DDH-2 were prepared with the cell line exhibiting the greatest resistance to cisplatin (A549) resulting in marked decreases in the DDH isoforms as assessed by real-time PCR, western blot and enzymatic activity. The DDH-1 knockout was far more sensitive to cisplatin than the DDH-2 knockout.

Conclusion: Thus, sensitivity to cisplatin appeared to be associated with DDH levels in epithelial lung cancer cell lines with the DDH-1 isoform producing the greatest effect. Results in keeping with transfection experiments with ovarian and other cell lines.

In plain English

This was a laboratory study of six human lung cancer cell lines grown in dishes. It did not study people or asbestos exposure. One line, H226, listed by its supplier as mesothelioma/squamous cell, was judged by staining to be of mesothelial cell origin. The authors tested how well the platinum drugs cisplatin and oxaliplatin killed the cells, and they measured several proteins previously linked to drug resistance. HO-1, 14-3-3zeta, GRP78, AKT and ERCC1 showed no association, or only poor correlation, with cisplatin killing. In the four epithelial non-small-cell lines, lower levels of the enzyme dihydrodiol dehydrogenase (DDH) went with less cisplatin resistance. This did not hold for the small-cell line DMS114 or the mesothelial line H226, which had low DDH but relatively high cisplatin resistance. H226 appeared sensitive to oxaliplatin. Reducing DDH-1 in the most resistant line, A549, lowered its cisplatin resistance to 0.53 (colony assay) and 0.40 (MTT assay) of the original. Reducing DDH-2 had a smaller effect (0.74 and 0.61). The authors concluded that cisplatin sensitivity appeared associated with DDH only in the epithelial lines.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) study of human cancer cell lines: drug-killing assays, protein and RNA measurements, and gene knockdown experiments
• Who was studied: Six human lung cancer cell lines obtained from ATCC: A549, H520, H460, H23 (epithelial non-small-cell), DMS114 (small-cell/neuroendocrine) and H226 (ATCC designation squamoid/mesothelioma, judged by staining to be of mesothelial cell origin). Two ovarian cancer lines (2008, A2780) were used for comparison in the cisplatin assays.
• Exposure: No asbestos exposure was studied. The cell lines were treated in the laboratory with the platinum chemotherapy drugs cisplatin and oxaliplatin.
• Main results:
  • In the mesothelial cell line H226, the cells appeared resistant to cisplatin, at a level similar to the H520 and H460 lines.
  • The mesothelial cell line H226 appeared sensitive to oxaliplatin.
  • Across the six cell lines, levels of HO-1, 14-3-3zeta and GRP78 showed no association with cisplatin resistance, and AKT levels showed poor correlation.
  • In the four epithelial non-small-cell lines, decreased total DDH (and to a lesser extent DDH-1) was associated with decreased cisplatin resistance.
  • In the small-cell line DMS114 and the mesothelial line H226, DDH levels were low but cisplatin resistance was relatively high, so there was little correlation.
  • Nuclear staining for ERCC1 in the cell lines correlated poorly with cisplatin killing.
  • In A549 cells with DDH-1 knocked down (A8n3), resistance to cisplatin relative to parental A549 cells was 0.53 by colony-forming assay and 0.40 by MTT assay (P less than 0.05 for both).
  • In A549 cells with DDH-2 knocked down (A7n1), resistance to cisplatin relative to parental A549 cells was 0.74 by colony-forming assay and 0.61 by MTT assay (P less than 0.05 for both). This was a lesser effect than the DDH-1 knockdown.
• The authors' conclusion: The authors concluded that cisplatin sensitivity appeared to be associated with DDH expression only in the four epithelial lung cancer cell lines, and not in the neuroendocrine/small-cell or mesothelioma-derived line. They reported that the DDH-1 knockdown had the greatest effect.
• Limitations the authors state:
  • The authors stated that how DDH produces its effect is unknown, and that no studies have yet shown a direct interaction with cisplatin.
  • The authors stated that whether DDH expression has a clinical role in lung cancer had not yet been determined.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Chemotherapy, Lung Cancer, Mesothelioma, Immunohistochemistry, Cisplatin.

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