An anti-cancer binary system activated by bacteriophage HK022 Integrase

Abstract

ABSTRACTCancer gene therapy is a great promising tool for cancer therapeutics due to the specific targeting based on the cancerous gene expression background. Binary systems based on site-specific recombination are one of the most effective potential approaches for cancer gene therapy. In these systems, a cancer specific promoter expresses a site-specific recombinase/integrase that in turn controls the expression of a toxin gene. In the current study, we have developed a new HK022 bacteriophage Integrase (Int) based binary system activating a Diphtheria toxin (DTA) gene expression specifically in cancer cells. We have demonstrated the efficiency, and the high specificity of the systemin vitroin cell cultures andin vivoin a lung cancer mouse model. Strikingly, different apoptotic and anti-apoptotic factors demonstrated a remarkable efficacy killing capability of the Int-based binary system compared to the conventionalhTERT-DTAmono system in the LLC-Kat lung cancer mice model; we observed that the activehTERTpromoter down regulation by the transcription factors Mad-1 is the cornerstone of this phenomenon. The new Int-based binary system offers advantages over already known counterparts and may therefore be developed into a safer and efficient cancer treatment technology.