Adenoviral delivery of A-FOS, an AP-1 dominant negative, selectively inhibits drug resistance in two human cancer cell lines.
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, namedAdA-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.
Bonovich
Maria
M
Laboratory of Metabolism, Medicine Branch, National Cancer Institute, Bethesda, Maryland 20892, USA.
Olive
Michelle
M
Reed
Eddie
E
O'Connell
Brian
B
Vinson
Charles
C
D000256:Adenoviridae / Q000235:genetics*; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003114:Colony-Forming Units Assay; D017931:DNA Primers / Q000737:chemistry; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D005799:Genes, Dominant; D016762:Genes, fos / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D006801:Humans; D007124:Immunoenzyme Techniques; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D016133:Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D018808:Transcription Factor AP-1 / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D017931:DNA Primers; D018808:Transcription Factor AP-1; D002945:Cisplatin