Resistance to platinum-based chemotherapy in lung cancer cell lines

Cancer Chemother Pharmacol. 2010 Nov;66(6):1103-11. doi: 10.1007/s00280-010-1268-2. Epub 2010 Feb 21.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma / drug therapy
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Blotting, Western
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Small Cell / drug therapy
  • Carcinoma, Squamous Cell / drug therapy
  • Cell Line, Tumor
  • Cisplatin / pharmacology
  • Drug Resistance, Neoplasm*
  • Humans
  • Hydroxysteroid Dehydrogenases / genetics
  • Immunohistochemistry
  • Inhibitory Concentration 50
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Mesothelioma / drug therapy
  • Organoplatinum Compounds / pharmacology
  • Oxaliplatin
  • Platinum Compounds / pharmacology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Stem Cell Assay

Substances

  • Organoplatinum Compounds
  • Platinum Compounds
  • Oxaliplatin
  • Hydroxysteroid Dehydrogenases
  • AKR1C2 protein, human
  • Cisplatin