Synergistic anti-tumor effects of nitroreductase mutants and p53.

Abstract

The p53 gene therapy showed promising results for treatment of numerous cancers particularly in combination with chemotherapy or radiotherapy. Gene therapy combining two or more treatment options may lead to the synergistic effects between diverse therapies and provide many opportunities in our fight against cancer. This study focused on the effects of p53 combining with the suicide gene therapy, nitroreductase (NTR)/5-(aziridin-1-yl)-2,4 dinitrobenzamide, on different cancer cell lines. Effects of adenoviral expressing p53 alone or in combination with wild type (WT) NTR, NTR single mutant, F124N and two NTR double mutants, T41L/N71S and T41L/F70A on survival rate of A549, QU-DB, MCF-7, MDA-MB-468 and DU145 cancer cell lines were determined by MTT assay. Expressions of MDM2 and TP53 transcripts were then assessed by quantitative real-time polymerase chain reaction in p53, NTR and combination of p53 with NTR infected cell lines. According to the results, combination of p53 with NTR double mutant, T41L/F70A or NTR single mutant F124N, showed statistically significant decrease in vitality of all cancer cell lines studied compared with status of IC 50 from p53 or WT NTR and other NTR mutants alone (P < 0.05). Expressions of TP53 and MDM2 were downregulated in all T41L/F70A infected cells except for MCF-7. Combination of T41L/F70A NTR with p53 may have more advantages for treatment of different types of cancers compared to the other NTRs and p53 alone. The present study results may open new windows for getting desired outcome in gene therapy of different types of cancer.