Anti-Tumor Effect of Heat-Killed Bifidobacterium bifidum on Human Gastric Cancer through Akt-p53-Dependent Mitochondrial Apoptosis in Xenograft Models

• Published in: International journal of molecular sciences 2022-09, Vol.23 (17), p.9788
• Main Authors: Kim, SukJin, Lee, Hwan Hee, Choi, Wonhyeok, Kang, Chang-Ho, Kim, Gun-Hee, Cho, Hyosun
• Format: Article
• Language: English
• Subjects: AKT protein; Animal models; Apoptosis; BAX protein; Bifidobacterium; Biocompatibility; Cancer therapies; Caspase-3; Caspase-9; Cell culture; Cell cycle; Chemotherapy; Colorectal cancer; Cytotoxicity; Disease prevention; Flow cytometry; Gastric cancer; Heat; Immune system; Immunohistochemistry; Inflammation; Kinases; Lactobacillus; Microorganisms; Mitochondria; Mixtures; Oral administration; p53 Protein; paraprobiotics; Poly(ADP-ribose) polymerase; Signal transduction; Staining; Strains (organisms); Tumors; Western blotting; xenograft; Xenografts; Xenotransplantation
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23179788

Paraprobiotics, inactivated microbial cells, regulate immune system and exhibit antioxidant and anti-inflammatory activities in patients with weakened immunity or the elderly. This study evaluated the anti-tumor effects of heat-killed Bifidobacterium and Lactobacillus on human gastric cancer MKN1 cells in vitro and in vivo in xenograft animal models. First, cytotoxicity and apoptosis in MKN1 cells of 11 different heat-killed Bifidobacterium or Lactobacillus strains were examined using the MTT assay or flow cytometry, respectively. Then, BALB/c nude mice xenograft animal models were implanted with human gastric cancer MKN1 cells and orally administered a selected single or a mixture of heat-killed bacterial strains to investigate their inhibitory effect on tumor growth. In addition, the expression of p-Akt, p53, Bax, Bak, cleaved caspase-9, -3, and PARP in the tumor tissues was analyzed using Western blotting assay or immunohistochemistry staining. The results show that heat-killed B. bifidum MG731 (MG731), L. reuteri MG5346 (MG5346), and L. rhamnosus MG5200 (MG5200) induced relatively greater apoptosis than other strains in MKN1 cells. Oral administration of a single dose or a mixture of MG731, MG5346, or MG5200 significantly delayed tumor growth, and MG731 had the most effective anti-tumor effect in the xenograft model. Protein expression of p-Akt, p53, Bax, cleaved caspase-3 and -9, and PARP in tumors derived from the xenograft model correlated with the results of the immunohistochemistry staining.