Abstract
BackgroundColorectal 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.MethodsSRB 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.ResultsFerrichrome 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.ConclusionsFerrichrome 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.
Highlights
Colorectal cancers develop through several pathways, including the adenoma–carcinoma sequence and colitis-associated carcinogenesis
The present study investigated the anti-tumor effect of ferrichrome, which was detected in the conditioned media of the probiotic L. casei as a mediator of the bacterial anti-tumor function, on colorectal cancer model using the patient-derived organoids and colitis-associated carcinogenesis model
A previous investigation showed that damage inducible transcript 3 (DDIT3) is a key transcriptional factor that induces the apoptotic pathway [21, 22] by binding the promoter of death receptors (DRs), including DR4 and DR5, to induce apoptosis through the BAX-BAKmediated mitochondrial pathways [23], illustrating that the anti-tumor effect of ferrichrome is mediated by the induction of DDTI3 in cancer cells
Summary
Colorectal cancers develop through several pathways, including the adenoma–carcinoma sequence and colitis-associated carcinogenesis. We investigated the anti-tumor effects of ferrichrome on precancerous conditions and cancer cells associated with sporadic as well as colitis-associated colorectal cancer. Several representative pathways, including the adenoma-carcinoma sequence and colitis-associated pathways, are involved in the development and progression of colorectal cancer [9, 10]. Alteration of the adenomatous polyposis coli (APC) gene is an initial event in adenomacarcinoma sequence, followed by a k-ras gene mutation and subsequently alterations of the p53 and Deleted in Colorectal Cancer (DCC) genes [11]. The alteration of the p53 function is thought to be an initial event in the colitis-associated pathway, followed by a k-ras gene mutation and alteration of the APC gene [12], suggesting that the process of cancer development differs among these pathways
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