Colorectal Cancer Therapy Using a Pediococcus pentosaceus SL4 Drug Delivery System Secreting Lactic Acid Bacteria-Derived Protein p8.

Abstract

Despite decades of research into colorectal cancer (CRC), there is an ongoing need for treatments that are more effective and safer than those currently available. Lactic acid bacteria (LAB) show beneficial effects in the context of several diseases, including CRC, and are generally regarded as safe. Here, we isolated a Lactobacillus rhamnosus (LR)-derived therapeutic protein, p8, which suppressed CRC proliferation. We found that p8 translocated specifically to the cytosol of DLD-1 cells. Moreover, p8 down-regulated expression of Cyclin B1 and Cdk1, both of which are required for cell cycle progression. We confirmed that p8 exerted strong anti-proliferative activity in a mouse CRC xenograft model. Intraperitoneal injection of recombinant p8 (r-p8) led to a significant reduction (up to 59%) in tumor mass when compared with controls. In recent years, bacterial drug delivery systems (DDSs) have proven to be effective therapeutic agents for acute colitis. Therefore, we aimed to use such systems, particularly LAB, to generate the valuable therapeutic proteins to treat CRC. To this end, we developed a gene expression cassette capable of inducing secretion of large amounts of p8 protein from Pediococcus pentosaceus SL4 (PP). We then confirmed that this protein (PP-p8) exerted anti-proliferative activity in a mouse CRC xenograft model. Oral administration of PP-p8 DDS led to a marked reduction in tumor mass (up to 64%) compared with controls. The PP-p8 DDS using LAB described herein has advantages over other therapeutics; these advantages include improved safety (the protein is a probiotic), cost-free purification, and specific targeting of CRC cells.

• Authors: Byung Chull An, Yongku Ryu, Yeo-Sang Yoon, Oksik Choi, Ho Jin Park, Tai Yeub Kim, Song-In Kim, Bong-Kyu Kim, Myung Jun Chung
• Journal: Molecules and cells (Mol Cells) Vol. 42 Issue 11 Pg. 755-762 (Nov 30 2019) ISSN: 0219-1032 [Electronic] Korea (South)
• PMID: 31707776 (Publication Type: Journal Article)

Chemical References

• Bacterial Proteins
• Recombinant Proteins

Topics

• Animals
• Bacterial Proteins (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects, genetics)
• Colorectal Neoplasms (drug therapy, genetics, metabolism)
• Drug Delivery Systems (methods)
• Gene Expression Regulation, Neoplastic (drug effects)
• HT29 Cells
• Humans
• Injections, Intraperitoneal
• Lacticaseibacillus rhamnosus (genetics, metabolism)
• Mice, Inbred BALB C
• Mice, Nude
• Pediococcus pentosaceus (metabolism)
• Recombinant Proteins (administration & dosage, metabolism)
• Xenograft Model Antitumor Assays (methods)