Bifidobacterium longum as an oral delivery system of endostatin for gene therapy on solid liver cancer

Abstract

To overcome difficulties that hampered widespread application of a specific delivery system in cancer gene therapy and to inhibit the growth of solid liver cancer, we utilized a strain of Bifidobacterium longum as a delivery system to transport an endostatin gene that can inhibit growth of tumor. The B. longum strain with the endostatin gene (B. longum-En) was taken orally by tumor-bearing nude mice through drencher preparation. The results showed that B. longum-En could strongly inhibit the growth of solid liver tumor in nude mice and prolong the survival time of tumor-bearing nude mice. Furthermore, tumor growth was inhibited more efficiently when the B. longum-En treatment included selenium. Enriching the B. longum-En treatment with selenium improves the activity of NK and T cells and stimulates the activity of IL-2 and TNF-alpha in BALB/c mice. These results suggest that B. longum may be a highly specific and efficient vector for transporting anticancer genes in cancer gene therapy.

Gene therapy for cancer: bacteria-mediated anti-angiogenesis therapy

“…In another study, Bifidobacterium longum was shown to efficiently deliver the anti-angiogenic protein endostatin to murine liver tumors and induce anti-tumor activity. 46,47 Furthermore, the anti-tumor effect was enhanced by co-administration of the same bacterial strain expressing tumor necrosis factor-related apoptosis inducing ligand. 48 These findings emphasize the need for combination therapy, in which multiple anti-tumor pathways are inhibited.…”

A new expression plasmid in Bifidobacterium longum as a delivery system of endostatin for cancer gene therapy

“…6 These plasmids, however, could not express foreign gene in Bifidobacterium, which hampered broader application of Bifidobacterium as a specific gene delivery system for cancer gene therapy although successful expressions of foreign gene in the Bifidobacterium have been reported. [7][8][9][10][11] Our previous studies demonstrated that pBV220, an E. coli-derived vector, could express foreign gene in B. adolescentis and B. longum. 9,10 However, it was found to be unstable in Bifidobacterium in the absence of selective antibiotics, which was particularly disadvantageous for prolonged and large-scale cultivation of the plasmid-bearing cells.…”

Bacteria in gene therapy: bactofection versus alternative gene therapy

“…After systemic application, its growth is limited to hypoxic areas such as the tissue of solid tumors. 8 Similar metabolism, and thus, similar applications have Salmonella enterica serovar typhimurium and S. choleraesuis in bacteria-mediated gene delivery. 19 The attenuation is achieved by deletion of not only aroA, aroC (both involved in synthesis of aromatic amino acids), but also ssaV (causes defects in the secretion apparatus encoded by a region of Salmonella pathogenicity island 2 -SPI2) or sifA (mutants cannot preserve the enveloping endosomal vacuoles).…”

“…The main advantages of bactofection are the simplicity of application [8][9][10][11] and the selectivity of gene transfer, which can be improved in the future by modulating, for example, organ-specific activity. 12 What is alternative gene therapy?…”

“…As a potent inhibitor of angiogenesis, endostatin inhibited the progress of the tumors, as the growth of solid tumors is dependent on oxygen and nutrient supply via new vessels. 8 Main advantages of this approach are inexpensiveness, target tissue specificity, easy and safe delivery in comparison to other gene therapy vectors or direct protein administration. In this very interesting study, another possibility of using bacteria therapeutically has been shown.…”