Specific driving of the suicide E gene by the CEA promoter enhances the effects of paclitaxel in lung cancer

Classical chemotherapy for lung cancer needs new strategies to enhance its antitumor effect. The cytotoxicity, nonspecificity, and low bioavailability of paclitaxel (PTX) limits their use in this type of cancer. Suicide gene therapy using tumor-specific promoters may increase treatment effectiveness. We used carcinoembryonic antigen (CEA) as a tumor-specific promoter to drive the bacteriophageEgene (pCEA-E) towards lung cancer cells (A-549 human and LL2 mice cell lines) but not normal lung cells (L132 human embryonic lung cell line), in association with PTX as a combined treatment. The study was carried out using cell cultures, tumor spheroid models (MTS), subcutaneous induced tumors and lung cancer stem cells (CSCs). pCEA-Einduced significant inhibition of A-549 and LL2 cell proliferation in comparison to L132 cells, which have lower CEA expression levels. Moreover, pCEA-Einduced an important decrease in volume growth of A-549 and LL2 MTS producing intense apoptosis, in comparison to L132 MTS. In addition, pCEA-Eenhanced the antitumor effects of PTX when combined, showing a synergistic effect. This effect was also observed in A-549 CSCs, which have been related to the recurrence of cancer. The in vivo study corroborated the effectiveness of the pCEA-E-PTX combined therapy, inducing a greater decrease in tumor volume compared to PTX and pCEA-Ealone. Our results suggest that the CEA promoter is an excellent candidate for directingEgene expression specifically towards lung cancer cells, and may be used to enhance the effectiveness of PTX against this type of tumor.