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Resistance to platinum-based chemotherapy in lung cancer cell lines

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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.

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Acknowledgments

The work was supported by the National Institutes of Health [Grant R01-CA098804, Funding Agency: National Cancer Institute].

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Authors and Affiliations

  1. North Shore-Long Island Jewish Health System, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA

    Jianli Chen & Henry Simpkins

  2. Department of Pathology and Laboratory Medicine, Staten Island University Hospital, Staten Island, NY, USA

    Jianli Chen & Henry Simpkins

  3. Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA, USA

    Nashwa Emara, Charalambos Solomides & Hemant Parekh

Authors
  1. Jianli Chen
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  2. Nashwa Emara
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  3. Charalambos Solomides
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  4. Hemant Parekh
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  5. Henry Simpkins
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Correspondence to Henry Simpkins.

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Chen, J., Emara, N., Solomides, C. et al. Resistance to platinum-based chemotherapy in lung cancer cell lines. Cancer Chemother Pharmacol 66, 1103–1111 (2010). https://doi.org/10.1007/s00280-010-1268-2

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  • DOI: https://doi.org/10.1007/s00280-010-1268-2

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