Telomerase transcriptional targeting of inducible bax/TRAIL gene therapy improves gemcitabine treatment of pancreatic cancer

Abstract

Currently, gemcitabine is approved as the first-line therapy for patients with locally advanced or metastatic pancreatic cancer. Unfortunately, because of pre-existing or acquired chemoresistance of most of the tumor cells, gemcitabine has failed to significantly improve the outcome for pancreatic carcinoma patients. The present study explored the possibility of sensitizing pancreatic cancer to gemcitabine chemotherapy by combining the chemotherapy with the proapoptotic genes Bax and TNF-related apoptosis-inducing ligand (TRAIL). We designed two tetracycline-inducible recombinant adenoviruses using the human telomerase reverse transcriptase (hTERT) promoter for transcriptional apoptogene targeting. Our data showed that treatment with the adenoviral systems resulted in high-level expression of Bax and TRAIL genes directly related to apoptosis induction, leading to a significant sensitization of resistant pancreatic tumor cells. Furthermore, treatment with Bax and TRAIL adenoviruses plus a suboptimal dose of gemcitabine resulted in significant tumor regression and prolongation of the experimental animal's life, in contrast to the weak retardation in tumor growth observed when gemcitabine alone was used. Additionally, using an orthotopic tumor model, we showed the usefulness of a non-invasive whole-body optical imaging for real-time evaluation of therapeutic efficacy. Together, these findings suggest that hTERT-targeted proapoptotic gene expression in combination with gemcitabine may be a potential therapeutic strategy for treatment of pancreatic adenocarcinoma.