Synergistic antitumoral effects of human telomerase reverse transcriptase-mediated dual-apoptosis-related gene vector delivered by orally attenuated Salmonella enterica Serovar Typhimurium in murine tumor models.
Salmonella enterica Serovar Typhimurium (S. typhimurium), a facultative anaerobe, has been reported to be capable of both selectively amplifying and expressing exogenous genes within tumors. In addition, previous studies have demonstrated that the human telomerase reverse transcriptase (hTERT) promoter could confine gene expression strictly to the telomerase-positive cancer cells. In the present study, we used attenuated S. typhimurium as a carrier to deliver a eukaryotic expression vector (pSNhTS) that contains the second mitochondria-derived activator of caspases (Smac) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) genes under the control of the hTERT promoter. The results of in vitro experiments showed that Smac could enhance TRAIL-induced apoptosis in tumor cells and the hTERT promoter could drive specific gene expression in tumor cells, but not in normal cells. In vivo data in mice indicated that salmonella-mediated exogenous gene expression could persist for at least 14 days in tumors. Furthermore, S.L./SNhTS (S. typhimurium carrying the pSNhTS) was orally administered into mice bearing tumors, and its antitumoral effect was evaluated. It was observed that S.L./SNhTS significantly inhibited tumor growth by 70-90% and prolonged the survival of mice. This strong antitumoral activity achieved by S.L./SNhTS was due to the synergistic antitumoral properties of Smac and TRAIL-recombinant proteins. Our data also support the idea that the hTERT promoter could be an excellent candidate for cancer-specific therapy and S. typhimurium appeared to be a promising strategy for the treatment of solid tumors.
Fu
Wei
W
State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University, Shanghai, China.
Chu
Liang
L
Han
Xinwei
X
Liu
Xinyuan
X
Ren
Daming
D
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012486:Salmonella typhimurium / Q000235:genetics / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000276:immunology*; D019098:Telomerase / Q000235:genetics; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D017931:DNA Primers; C499605:Diablo protein, mouse; D024101:Mitochondrial Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D014613:Vaccines, Attenuated; C509186:TERT protein, human; D019098:Telomerase