Background: Berberine (BBR) has been extensively reported to inhibit colorectal cancer (CRC) development, though its bioavailability is poor. Nowadays, an increasing number of studies have shown that BBR significantly accumulates in the intestines and could regulate gut microbiota in obesity. The purpose of this study was to further explore the effects of BBR on gut microbiota in Apc min/+ mice receiving a high fat diet (HFD). Methods: Apc min/+ mice received either HFD alone or HFD and BBR for 12 weeks. The intestinal tissues were collected to evaluate the efficiency of BBR on neoplasm development by hematoxylin and eosin staining. Meanwhile, immunohistochemistry was conducted to investigate the effects of BBR on cyclin D1 and β-catenin in colon tissues. Fecal samples were subjected to 16S rRNA sequencing. Results: BBR significantly reduced intestinal tumor development and altered the structure of gut microbiota in Apc min/+ mice fed with an HFD. At the phylum level, it was able to significantly inhibit the increase in Verrucomicrobia. At the genus level, it was able to suppress Akkermansia and elevate some short chain fat acid (SCFA)-producing bacteria. Conclusions: BBR significantly alleviated the development of CRC in Apc min/+ mice fed with HFD and restored the enteric microbiome community.

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Background and Purpose: Signal transducer and activator of transcription 3 (STAT3) factor is associated with the development and progression of numerous types of human cancer. STAT3 activation is involved in metastasis. However, no STAT3 inhibitor has been used therapeutically. Hence, we syntheised a novel, potent and small-molecule inhibitor of STAT3, LL1, and studied its antitumour effects and investigated its mechanism of action in two tumour models.Experimental Approach: Using structure-based drug design method, based on the crystal structure of STAT3 protein, we identified a potent STAT3 inhibitor (LL1) targeting STAT3 SH2 domain and characterized its therapeutic properties and potential toxicity in vitro and in vivo using the MTT assay, colony formation assay, histological, immunohistochemical, flow cytometric analysis, and tumour xenograft model.Key Results: LL1 is highly selective among STATs family members and specifically inhibits phosphorylation of STAT3 Tyr-705 site, blocking the whole transmission process of STAT3 signalling. LL1 inhibited proliferation, colony formation, migration, and invasion of colonic cell lines. STAT3 is orally available to animals and suppresses tumour growth and metastasis in a dosage level compatible to clinical applications. Importantly, it does not cause significant toxicity at several times the effective dose.Conclusions and Implications: LL1 inhibits tumour growth and metastasis by blocking STAT3 signalling pathway. LL1 could be a promising therapeutic drug candidate for colorectal cancer by inhibiting the STAT3 activation.

Signal transducers and activators of transcription 3 (STAT3) represent a transcription factor that is constitutively activated in various cancers. Numerous studies have shown that STAT3 plays crucial roles in cell proliferation and survival, angiogenesis, tumor-promoting inflammation, and suppression of antitumor host immune response in the tumor microenvironment. In this study, we investigated a novel inhibitor, called -6b, to target STAT3 in colorectal cancer cells. The influence of 5Br-6b on the proliferation of colorectal cell lines SW480 and HCT116 was evaluated using an 3-(4, 5-dimethylthiazolyl)-2 and 5-diphenyltetrazolium bromide assay. We detected cell apoptosis after the treatment of 5Br-6b by flow cytometry. In addition, 5Br-6b caused the cleavage of caspase-3 and decreased the expression of Bcl-2. Cancer cell invasion and migration were measured by transwell and wound-healing assay. The potential mechanism was evaluated by western blotting and immunofluorescence. The results show that 5Br-6b inhibits the activation of STAT3, and decreases the expression of its target genes that regulate cell proliferation, migration, and apoptosis. Thus, 5Br-6b is a promising therapeutic drug candidate for colorectal cancer by inhibiting persistent STAT3 signaling.