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

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, 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.