s-adenosylhomocysteine and Colorectal-Neoplasms

Induction of oxidative stress and reactive oxygen species (ROS) mediated-apoptosis have been utilized as effective strategies in anticancer therapy. Macranthoidin B (MB) is a potent inducer of ROS-mediated apoptosis in cancer, but its mechanism of action is poorly understood.. Superoxide production with MB exposure in colorectal cancer (CRC) cells was measured using lucigenin chemiluminescence and real-time PCR. MB's inhibitory effect on proliferation and viability of CRC cells was determined by proliferation assays. MB's effect on apoptosis of CRC cells was determined by Western blotting and annexin V-FITC/PI staining. MB's effect on the growth of CRC xenografts in mice was assessed. An established metabolomics profiling platform combining ultra-performance liquid chromatography-tandem mass spectrometry (LC-MS) with gas chromatography-mass spectrometry (GC-MS) was performed to determine MB's effect on total metabolite variation in CRC cells.. We found that MB increases ROS generation via modulating key metabolic pathways. Using metabolomics profiling platform combining LC-MS with GC-MS, a total of 236 metabolites were identified in HCT-116 cells in which 31 metabolites were determined to be significantly regulated (p ≤ 0.05) after MB exposure. A number of key metabolites revealed by metabolomics analysis include glucose, fructose, citrate, arginine, phenylalanine, and S-adenosylhomocysteine (SAH), suggesting specific modulation of metabolism on carbohydrates, amino acids and peptides, lipids, nucleotide, cofactors and vitamins in HCT-116 CRC cells with MB treatment highly associated with apoptosis triggered by enhanced ROS and activated caspase-3.. Our results demonstrate that MB represses CRC cell proliferation by inducing ROS-mediated apoptosis.

Topics: Amino Acids; Animals; Apoptosis; Carbohydrate Metabolism; Caspase 3; Chromatography, High Pressure Liquid; Colorectal Neoplasms; Discriminant Analysis; Gas Chromatography-Mass Spectrometry; Glutathione Peroxidase; HCT116 Cells; Humans; Least-Squares Analysis; Lipid Metabolism; Mass Spectrometry; Metabolome; Metabolomics; Mice; Mice, Nude; Oleanolic Acid; Reactive Oxygen Species; S-Adenosylhomocysteine; Saponins; Superoxide Dismutase; Transplantation, Heterologous

Colorectal cancer (CRC) is ranked the third most common cancer in human worldwide. However, the exact mechanisms of CRC are not well established. Furthermore, there may be differences between mechanisms of CRC in the Asian and in the Western populations. In the present study, we utilized a liquid chromatography-mass spectrometry (LC-MS) metabolomic approach supported by the 16S rRNA next-generation sequencing to investigate the functional and taxonomical differences between paired tumor and unaffected (normal) surgical biopsy tissues from 17 Malaysian patients. Metabolomic differences associated with steroid biosynthesis, terpenoid biosynthesis and bile metabolism could be attributed to microbiome differences between normal and tumor sites. The relative abundances of Anaerotruncus, Intestinimonas and Oscillibacter displayed significant relationships with both steroid biosynthesis and terpenoid and triterpenoid biosynthesis pathways. Metabolites involved in serotonergic synapse/ tryptophan metabolism (Serotonin and 5-Hydroxy-3-indoleacetic acid [5-HIAA]) were only detected in normal tissue samples. On the other hand, S-Adenosyl-L-homocysteine (SAH), a metabolite involves in methionine metabolism and methylation, was frequently increased in tumor relative to normal tissues. In conclusion, this study suggests that local microbiome dysbiosis may contribute to functional changes at the cancer sites. Results from the current study also contributed to the list of metabolites that are found to differ between normal and tumor sites in CRC and supported our quest for understanding the mechanisms of carcinogenesis.

Topics: Adult; Aged; Bacteria; Chromatography, High Pressure Liquid; Colorectal Neoplasms; Female; High-Throughput Nucleotide Sequencing; Humans; Intestinal Mucosa; Male; Metabolomics; Microbiota; Middle Aged; Principal Component Analysis; RNA, Ribosomal, 16S; S-Adenosylhomocysteine; Sequence Analysis, DNA; Steroids; Tandem Mass Spectrometry; Terpenes

This study reports the influence of colorectal neoplasia on methylation intermediates and folate concentrations in human colonic mucosa, as well as systemic measures of folate status, to examine biomarkers and possible mechanisms of folate-related carcinogenesis.. A total of 47 patients were selected from those previously diagnosed with adenocarcinoma of the colorectum undergoing surgery. For each individual, we obtained a biopsy of the adenocarcinoma and a biopsy of normal appearing mucosa, to perform an intra-individual comparison.. The 'methylation' ratio (S-adenosylmethionine/S-adenosylhomocysteine (SAH)) was lower in pathological tissue vs normal mucosa (P=0.08), mainly due to a much higher SAH concentration (P<0.005). Colonic folate concentration was significantly diminished in malignant tissue (P<0.0001). Plasma homocysteine concentration was within the normal to high range, and folate and vitamin B12 plasma concentrations were within the low to normal range as compared with normative values.. Our results contribute to the hypothesis that altered DNA methylation and methyl metabolism is associated with colorectal neoplasia.

Topics: Adenocarcinoma; Aged; Colon; Colorectal Neoplasms; DNA Methylation; Female; Folic Acid; Homocysteine; Humans; Intestinal Mucosa; Male; Nutritional Status; S-Adenosylhomocysteine; S-Adenosylmethionine