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Adenoviral delivery of A-FOS, an AP-1 dominant negative, selectively inhibits drug resistance in two human cancer cell lines

Cancer Gene Therapy volume 9, pages 62–70 (2002)Cite this article

Abstract

Activator protein-1 (AP-1) transcription factor has been linked to chemotherapeutic resistance. To assess the clinical efficacy of AP-1 inhibition toward reversing drug resistance, we have developed an adenovirus expressing a dominant negative that inhibits AP-1 DNA binding, named AdA-FOS. We examined the consequence of AdA-FOS infection on two paired human cancer cell lines, each pair consisting of a parental cell and the drug-resistant derivative. The first pair of cells is the parental human ovarian cancer cell line A2780 and the cisplatin-resistant A2780/CP70 cell line. The second pair of cells is the parental epidermal carcinoma cell line KB8 and the multidrug-resistant (mdr) KB85 cell line. Because of an association of up-regulated AP-1 activity with their drug resistance, these cell lines were considered good targets of AdA-FOS therapy. Following infection of the drug-sensitive and drug-resistant cells, we observed a significant decrease in cell viability of KB85 and A2780/CP70 cells at drug doses normally not lethal to the cell. The parental cell lines, A2780 and KB8 cells, were not similarly affected by AdA-FOS. This decrease in viability was specific to AdA-FOS as an adenovirus control (Advector) did not reverse drug resistance. Although the efficiency of AdA-FOS in therapy would need to be further analyzed with other cisplatin-resistant and mdr cell lines, these results suggest that AP-1 is a therapeutic molecular target and that inhibition of AP-1 DNA binding may be of clinical value in treating chemotherapeutic resistance.

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Acknowledgements

We thank Christine Hrycyna and Michael Gottesman for help with the KB cells, Cheryl Cross and Claire Radecki for help on this project, and Alain Mir for comments on the manuscript.

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Authors and Affiliations

  1. Laboratory of Metabolism, Medicine Branch, National Cancer Institute, National Institute, Bethesda, 20892, Maryland, USA

    Maria Bonovich, Michelle Olive & Charles Vinson

  2. Developmental Therapeutics Department, Medicine Branch, National Cancer Institute, Bethesda, 20892, Maryland, USA

    Eddie Reed

  3. School of Dental Science, Trinity College, 2, Dublin, Ireland

    Brian O'Connell

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  1. Maria Bonovich
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  2. Michelle Olive
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  3. Eddie Reed
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  4. Brian O'Connell
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  5. Charles Vinson
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Correspondence to Charles Vinson.

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Bonovich, M., Olive, M., Reed, E. et al. Adenoviral delivery of A-FOS, an AP-1 dominant negative, selectively inhibits drug resistance in two human cancer cell lines. Cancer Gene Ther 9, 62–70 (2002). https://doi.org/10.1038/sj.cgt.7700409

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