Anti-tumoral effect of the mitochondrial target domain of Noxa delivered by an engineered Salmonella typhimurium

Bacterial cancer therapy relies on the fact that several bacterial species are capable of targeting tumor tissue and that bacteria can be genetically engineered to selectively deliver therapeutic proteins of interest to the targeted tumors. However, the challenge of bacterial cancer therapy is the r...

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Bibliographic Details
Published in:PloS one 2014-01, Vol.9 (1), p.e80050
Main Authors: Jeong, Jae-Ho, Kim, Kwangsoo, Lim, Daejin, Jeong, Kwangjoon, Hong, Yeongjin, Nguyen, Vu H, Kim, Tae-Hyoung, Ryu, Sangryeol, Lim, Jeong-A, Kim, Jae Il, Kim, Geun-Joong, Kim, Sun Chang, Min, Jung-Joon, Choy, Hyon E
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Anticancer properties
Antineoplastic Agents - pharmacology
Apoptosis
Arabinose
Arabinose - pharmacology
Bacteria
Bacteriolysis - drug effects
Biochemistry
Biology
Cancer
Cancer therapies
Cell death
Cell Death - drug effects
Cell Line, Tumor
Cell-Penetrating Peptides - chemistry
Cell-Penetrating Peptides - pharmacology
Cloning
Colon
Colon cancer
E coli
Escherichia coli
Gene Transfer Techniques
Genes
Genetic Engineering
Genetically modified organisms
Health aspects
Humans
Lysis
Medical schools
Medicine
Methods
Mice
Mitochondria
Mitochondria - drug effects
Mitochondria - metabolism
Molecular Sequence Data
Monosaccharides
Nuclear medicine
Peptides
Phages
Phenotype
Plasmids
Plasmids - metabolism
Potassium
Potassium channels (voltage-gated)
Protein Structure, Tertiary
Proteins
Proto-Oncogene Proteins c-bcl-2 - chemistry
Salmonella
Salmonella Typhimurium
Salmonella typhimurium - genetics
Science
Therapy
Tissue Distribution - drug effects
Tumor cells
Tumors
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Summary:Bacterial cancer therapy relies on the fact that several bacterial species are capable of targeting tumor tissue and that bacteria can be genetically engineered to selectively deliver therapeutic proteins of interest to the targeted tumors. However, the challenge of bacterial cancer therapy is the release of the therapeutic proteins from the bacteria and entry of the proteins into tumor cells. This study employed an attenuated Salmonella typhimurium to selectively deliver the mitochondrial targeting domain of Noxa (MTD) as a potential therapeutic cargo protein, and examined its anti-cancer effect. To release MTD from the bacteria, a novel bacterial lysis system of phage origin was deployed. To facilitate the entry of MTD into the tumor cells, the MTD was fused to DS4.3, a novel cell-penetrating peptide (CPP) derived from a voltage-gated potassium channel (Kv2.1). The gene encoding DS4.3-MTD and the phage lysis genes were placed under the control of PBAD , a promoter activated by L-arabinose. We demonstrated that DS4.3-MTD chimeric molecules expressed by the Salmonellae were anti-tumoral in cultured tumor cells and in mice with CT26 colon carcinoma.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0080050