bix-01294 and Colorectal-Neoplasms

During the development of colorectal cancer, tumor cells will generate some cancer stem cells with self-renewal ability because they adapt to the environment. Therefore, in the treatment of colorectal cancer, it has certain potential clinical application value to effectively inhibit cancer stem cells. A small molecule EHMT-2 inhibitor, BIX-01294, was evaluated for its activity in inhibiting cancer stem cells in human colorectal cancer by in vitro and in vivo experiments. Transcriptome analysis was performed on BIX-01294 treated cells for holistic analysis to elucidate how BIX-01294 inhibits the expression of genes related to cancer stem cells. The results show that BIX-01294 significantly inhibited the proliferative phenotype of human colorectal cancer in vivo and in vitro, reduced the proportion of cancer stem cells, and inhibited some stemness-related gene. Morever, it is synergistic with 5-fluorouracil in inhibiting the proliferation of colorectal cancer. In summary, EHMT-2 is a novel target of anti-tumor drugs. The combination of BIX-01294 and 5-fluorouracil has a synergistic therapeutic effect on human colorectal cancer.

Topics: Animals; Azepines; Biomarkers, Tumor; Cell Line, Tumor; Cell Movement; Cell Proliferation; Colorectal Neoplasms; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Histocompatibility Antigens; Histone-Lysine N-Methyltransferase; Humans; Mice, Inbred BALB C; Mice, Nude; Neoplastic Stem Cells; Quinazolines; Receptors, G-Protein-Coupled

Uridine diphosphate-glucuronosyltransferase (UGT) 2B7, as one of significant drug enzymes, is responsible on the glucuronidation of abundant endobiotics or xenobiotics. We here report that it is markedly repressed in the tumor tissues of colorectal carcinoma (CRC) patients. Accordingly, morphine in CRC cells will stimulate the expression of its main metabolic enzyme, UGT2B7 during tolerance generation by activating the positive signals in histone 3, especially for trimethylated lysine 27 (H3K4Me3) and acetylated lysine 4 (H3K27Ac). Further study reveals that brain-derived neutrophilic factor (BDNF), a secretory neurotrophin, enriched in CRC can interact and inhibit UGT2B7 by primarily blocking the positive signals of H3K4Me3 as well as activating H3K27Ac on the promoter region of UGT2B7. Meanwhile, BDNF repression attributes to the sensitizations of main core factors in poly-comb repressive complex (PRC) 1 rather than PRC2 as the reason of the depression of SUZ12 in the later complex. Besides that, the productions of two main morphine glucuronides are both increased in the BDNF deficient or TSA and BIX-01294 treated morphine tolerance-like HCT-116 cells. On the same condition, active metabolite, morphine-6-glucuronide (M6G) was accumulated more than inactive M3G. Our findings imply that enzymatic activity enhancement and substrate regioselective catalysis alteration of UGT2B7 may release morphine tolerance under the cure of tumor-induced pain.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Azepines; Brain-Derived Neurotrophic Factor; Cancer Pain; Cell Line, Tumor; Colorectal Neoplasms; Drug Tolerance; Epigenetic Repression; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Glucuronosyltransferase; Histocompatibility Antigens; Histone-Lysine N-Methyltransferase; Histones; Humans; Immunohistochemistry; Male; Middle Aged; Morphine; Morphine Derivatives; Neoplasm Proteins; Polycomb Repressive Complex 1; Polycomb Repressive Complex 2; Promoter Regions, Genetic; Quinazolines; RNA Interference; RNA, Small Interfering; Transcription Factors; Up-Regulation