BACKGROUND: Colorectal cancers develop through several pathways, including the adenoma-carcinoma sequence and colitis-associated carcinogenesis. An altered intestinal microflora has been reported to be associated with the development and progression of colorectal cancer via these pathways. We identified Lactobacillus casei-derived ferrichrome as a mediator of the bacterial anti-tumor effect of colorectal cancer cells through the upregulation of DDIT3. In this study, we investigated the anti-tumor effects of ferrichrome on precancerous conditions and cancer cells associated with sporadic as well as colitis-associated colorectal cancer. METHODS: SRB and MTT assays were performed to assess growth inhibition in vitro. Eighteen organoids were prepared from biopsy specimens obtained by colonoscopy. An AOM-DSS carcinogenesis model and xenograft model of colorectal cancer cells were generated for the assessment of the tumor suppressive effect of ferrichrome in vivo. RESULTS: Ferrichrome inhibited the cell growth of colorectal cancer cells in vitro and in in vivo xenograft models. Ferrichrome exerted a strong tumor-suppressive effect that was superior to that of currently available anti-tumor agents, including 5-FU and cisplatin, both in vitro and in vivo. The tumor-suppressive effect of the combination of ferrichrome and 5-FU was superior to that of single treatment with either drug. The tumor suppressive effects of ferrichrome were confirmed through the upregulation of DDIT3 in patient-derived organoids of adenoma and carcinoma. Ferrichrome inhibited the tumor progression in the AOM-DSS model while exhibiting no anti-inflammatory effect in the DSS-colitis model, suggesting that ferrichrome inhibited cancer cells, but not a precancerous condition, via the colitis-associated pathway. CONCLUSIONS: Ferrichrome exerts a tumor suppressive effect on precancerous conditions and cancer cells associated with sporadic as well as colitis-associated colorectal cancer. The anti-tumor effect of ferrichrome was mediated by the upregulation of DDIT3, and was superior to that of 5-FU or cisplatin. These results suggest that Lactobacillus brevis-derived ferrichrome may be a candidate anti-tumor drug for the treatment of colorectal neoplasms.
BACKGROUND:Colorectal cancers develop through several pathways, including the adenoma-carcinoma sequence and colitis-associated carcinogenesis. An altered intestinal microflora has been reported to be associated with the development and progression of colorectal cancer via these pathways. We identified Lactobacillus casei-derived ferrichrome as a mediator of the bacterial anti-tumor effect of colorectal cancer cells through the upregulation of DDIT3. In this study, we investigated the anti-tumor effects of ferrichrome on precancerous conditions and cancer cells associated with sporadic as well as colitis-associated colorectal cancer. METHODS:SRB and MTT assays were performed to assess growth inhibition in vitro. Eighteen organoids were prepared from biopsy specimens obtained by colonoscopy. An AOM-DSS carcinogenesis model and xenograft model of colorectal cancer cells were generated for the assessment of the tumor suppressive effect of ferrichrome in vivo. RESULTS: Ferrichrome inhibited the cell growth of colorectal cancer cells in vitro and in in vivo xenograft models. Ferrichrome exerted a strong tumor-suppressive effect that was superior to that of currently available anti-tumor agents, including 5-FU and cisplatin, both in vitro and in vivo. The tumor-suppressive effect of the combination of ferrichrome and 5-FU was superior to that of single treatment with either drug. The tumor suppressive effects of ferrichrome were confirmed through the upregulation of DDIT3 in patient-derived organoids of adenoma and carcinoma. Ferrichrome inhibited the tumor progression in the AOM-DSS model while exhibiting no anti-inflammatory effect in the DSS-colitis model, suggesting that ferrichrome inhibited cancer cells, but not a precancerous condition, via the colitis-associated pathway. CONCLUSIONS: Ferrichrome exerts a tumor suppressive effect on precancerous conditions and cancer cells associated with sporadic as well as colitis-associated colorectal cancer. The anti-tumor effect of ferrichrome was mediated by the upregulation of DDIT3, and was superior to that of 5-FU or cisplatin. These results suggest that Lactobacillus brevis-derived ferrichrome may be a candidate anti-tumor drug for the treatment of colorectal neoplasms.
Authors: Simon J Leedham; Trevor A Graham; Dahmane Oukrif; Stuart A C McDonald; Manuel Rodriguez-Justo; Rebecca F Harrison; Neil A Shepherd; Marco R Novelli; Janusz A Z Jankowski; Nicholas A Wright Journal: Gastroenterology Date: 2008-11-07 Impact factor: 22.682
Authors: Alberto F Sobrero; Joan Maurel; Louis Fehrenbacher; Werner Scheithauer; Yousif A Abubakr; Manfred P Lutz; M Eugenia Vega-Villegas; Cathy Eng; Ernst U Steinhauer; Jana Prausova; Heinz-Josef Lenz; Christophe Borg; Gary Middleton; Hendrik Kröning; Gabriele Luppi; Oliver Kisker; Angela Zubel; Christiane Langer; Justin Kopit; Howard A Burris Journal: J Clin Oncol Date: 2008-04-07 Impact factor: 44.544
Authors: K W J Hoeben; L N van Steenbergen; A J van de Wouw; H J Rutten; D J van Spronsen; M L G Janssen-Heijnen Journal: Ann Oncol Date: 2012-11-07 Impact factor: 32.976
Authors: Aneta Sevcikova; Nikola Izoldova; Viola Stevurkova; Barbora Kasperova; Michal Chovanec; Sona Ciernikova; Michal Mego Journal: Int J Mol Sci Date: 2022-01-01 Impact factor: 5.923
Authors: Edgar Torres-Maravilla; Anne-Sophie Boucard; Amir Hossein Mohseni; Sedigheh Taghinezhad-S; Naima G Cortes-Perez; Luis G Bermúdez-Humarán Journal: Microorganisms Date: 2021-05-10