chiniofon and Colorectal-Neoplasms

Epigenetic activation of Wnt/β-catenin signaling plays a critical role in Wnt-induced tumorigenesis, notably in colorectal cancers. KDM3 and KDM4 histone demethylases have been reported to promote oncogenic Wnt signaling through demethylation of H3K9 on Wnt target gene promoters and are suggested to be potential therapeutic targets. However, potent inhibitors for these regulators are still not available. In addition, which family is most responsible for activation of Wnt target genes and Wnt-induced oncogenesis is not well documented, specifically in colorectal cancer. In this study, we characterized the functional redundancy and differences between KDM3 and KDM4 in regard to regulating Wnt signaling. Our data suggest that KDM3 may play a more essential role than KDM4 in regulating oncogenic Wnt signaling in human colorectal cancer. We also identified that IOX1, a known histone demethylase inhibitor, significantly suppresses Wnt target gene transcription and colorectal cancer tumorigenesis. Mechanistically, IOX1 inhibits the enzymatic activity of KDM3 by binding to the Jumonji C domain and thereby preventing the demethylation of H3K9 on Wnt target gene promoters. Taken together, our data not only identified the critical mechanisms by which IOX1 suppressed Wnt/β-catenin signaling and colorectal cancer tumorigenesis through inhibition of KDM3, but also suggested that IOX1 may represent an attractive small molecule lead for future drug design and discovery.

Topics: Animals; Carcinogenesis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Colorectal Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Hydroxyquinolines; Jumonji Domain-Containing Histone Demethylases; Mice, Nude; Neoplasm Invasiveness; Neoplastic Stem Cells; Transcription, Genetic; Wnt Proteins; Wnt Signaling Pathway

Chronic gut inflammation disposes to an increased risk of colitis-associated cancer. Chemoprevention is an attractive complementary strategy. We aimed to evaluate the chemopreventive effects of M10, a novel derivative of Myricetin, in the murine azoxymethane/dextran sodium sulfate model. Oral administration of M10 at 50-100 mg/kg once a day for consecutive 12 weeks significantly prevented ulcerative colitis (UC) and colorectal tumor. Pathological analysis of intestines showed that M10 reduced the degree of chronic inflammation and prevented the progression of colorectal tumorigenesis. Flow cytometry analysis of the immunocytes isolated from intraepithelial and lamina propria showed that M10 prevented the infiltration of myeloid-derived suppressor cells and increased CD8+T and CD4+T cells in colorectal tissues. Enzyme-linked immunosorbent analysis revealed the reduction of pro-inflammatory mediators granulocyte-macrophage colony-stimulating factor/macrophage colony-stimulating factor, IL-6 and TNF-α in colonic mucosa. Western blot assay also showed M10 prevention of the NF-κB/IL-6/STAT3 pathways and the biomarkers of inflammation and colorectal tumorigenesis. Electron microscopy analysis revealed that M10 prevent robust endoplasmic reticulum (ER) stress-induced autophagy in inflamed colonic mucosal cells. In conclusion, oral administration of Myricetin derivative M10 exerts chemoprevention of UC and colorectal tumor in mice. The mechanism of chemoprevention is associated with the reduction of biomarkers of chronic inflammation and proliferation through attenuating robust ER stress in inflamed colonic mucosal cells. M10 exerts chemoprevention activity without evidence of toxicity in mice. These results justify further evaluation of M10 in clinical trials. M10 could develop a promising regimen in the chemoprevention of colitis and colorectal cancer.

Topics: Alanine; Animals; Anticarcinogenic Agents; Colitis, Ulcerative; Colon; Colorectal Neoplasms; Disease Models, Animal; Endoplasmic Reticulum Stress; Flavonoids; Hydroxyquinolines; Inflammation; Inflammation Mediators; Interleukin-6; Intestinal Mucosa; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Signal Transduction; STAT3 Transcription Factor; Tumor Necrosis Factor-alpha

Irinotecan (CPT-11) is a prodrug that is used to treat metastatic colorectal cancer. It is activated to the topoisomerase poison SN-38 by carboxylesterases. SN-38 is metabolized to its inactive glucuronide, SN-38 glucuronide. The aim of this study was to determine, the reactivation of SN-38 from SN-38 glucuronide by beta-glucuronidase may represent a significant pathway of SN-38 formation.. The production of SN-38 from irinotecan and SN-38 glucuronide (2.4, 9.6 and 19.2 microm) was measured in homogenates of human colorectal tumour, and matched normal colon mucosa from 21 patients).. The rate of conversion of irinotecan (9.6 microm) was lower in tumour tissue than matched normal colon mucosa samples (0.30+/-0.14 pmol min-1 mg-1 protein and 0.77+/-0.59 pmol min-1 mg-1 protein, respectively; P<0.005). In contrast, no significant difference was observed in beta-glucuronidase activity between tumour and matched normal colon samples (4.56+/-6.9 pmol min-1 mg-1 protein and 3.62+/-2.95 pmol min-1 mg-1 protein, respectively, using 9.6 microm SN-38 glucuronide; P>0.05). beta-Glucuronidase activity in tumour correlated to that observed in matched normal tissue (r2>0.23, P<0.05), whereas this was not the case for carboxylesterase activity. At equal concentrations of irinotecan and SN-38 glucuronide, the rate of beta-glucuronidase-mediated SN-38 production was higher than that formed from irinotecan in both tumour and normal tissue (P<0.05). However, at concentrations that reflect the relative plasma concentrations observed in patients, the rate of SN-38 production via these two pathways was comparable.. Tumour beta-glucuronidase may play a significant role in the exposure of tumours to SN-38 in vivo.

Topics: Antineoplastic Agents, Phytogenic; Camptothecin; Carboxylesterase; Colorectal Neoplasms; Glucuronidase; Humans; Hydroxyquinolines; Irinotecan; Nitrophenols; Tumor Cells, Cultured