Recently, we reported a novel therapeutic probiotic-derived protein, p8, which has anti-colorectal cancer (anti-CRC) properties. In vitro experiments using a CRC cell line (DLD-1), anti-proliferation activity (about 20%) did not improve after increasing the dose of recombinant-p8 (r-p8) to >10 μM. Here, we show that this was due to the low penetrative efficiency of r-p8 exogenous treatment. Furthermore, we found that r-p8 entered the cytosol through endocytosis, which might be a reason for the low penetration efficiency. Therefore, to improve the therapeutic efficacy of p8, we tried to improve delivery to CRC cells. This resulted in endogenous expression of p8 and increased the anti-proliferative effects by up to 2-fold compared with the exogenous treatment (40 μM). Anti-migration activity also increased markedly. Furthermore, we found that the anti-proliferation activity of p8 was mediated by inhibition of the p53-p21-Cyclin B1/Cdk1 signal pathway, resulting in growth arrest at the G2 phase of the cell cycle. Taken together, these results suggest that p8 is toxic to cancer cells, shows stable expression within cells, and shows strong cancer suppressive activity by inducing cell cycle arrest. Therefore, p8 is a strong candidate for gene therapy if it can be loaded onto cancer-specific viruses.

Food-grade bacteria, including lactic acid bacteria (LAB), are safe to ingest and are not associated with development of disease. The impact of LAB on health has been studied in depth from a clinical perspective. Evidence suggests that LAB benefit health in several ways, including improving the balance between probiotic and harmful bacteria in the intestine, protecting against pathogen infections, and modulating host immunity in the gut. Recent publications show that LAB are safe biotherapeutics that exert positive effects against various cancer types, including colorectal cancer (CRC). CRC develops in intestine and, unless treated early, will invade the surrounding tissue and spread to other parts of the body. One intrinsic advantage of food-grade LAB is that they can be applied easily as oral medications and act as vehicles for bio-therapeutics, which can be delivered directly to the mucosal surface of the intestine. Consequently, a LAB-based drug delivery system (DDS) can have synergistic effects: the patient derives benefit from both the LAB and the therapeutic cargo. Furthermore, the localized effect of LAB-based DDS in the intestine would ensure targeted treatment at the site of disease; this has the benefits of requiring a lower dose of a drug, with fewer systemic side effects. In this review, we discuss the evidence supporting the beneficial effects of LAB-based DDS and its application to CRC.

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