investigator_user investigator user funding collaborators pending menu bell message arrow_up arrow_down filter layers globe marker add arrow close download edit facebook info linkedin minus plus save share search sort twitter remove user-plus user-minus
  • Project leads
  • Collaborators

Xenobiotic metabolism, cancer chemoprevention and cancer biomarkers – Rockville

Frank Gonzalez

1 Collaborator(s)

Funding source

National Cancer Institute (NIH)
St. John's wort (SJW) attenuates colorectal carcinogenesis in mice through suppression of inflammatory signaling: SJW is a widely used dietary supplement available over the counter. Components of SJW extract, such as, hypericin and hyperforin were found to attenuate neurotransmitters receptors which the main marketing point for the its use as an over-the-counter antidepressant. Hyperforin also triggers apoptosis of lung and the colon cancer cell lines, and consumption of SJW extract was associated with reduced risk of developing colorectal cancer. However, the underlying mechanism of this protection has not been determined. This is particularly important given the fact that SJW constituents and/or extracts were shown to increase the metabolism and compromise the efficacy of drugs including anti-cancer agents. The prophylactic effect of SJW extract on colorectal carcinogenesis was examined using the AOM-induced colorectal carcinogenesis mode. The impact of dietary supplementation of SJW extract on AOM-induced colorectal carcinogenesis was evaluated in mice. Mice were fed with either AIN-93G (control) diet or SJW extract-supplemented diet (SJW diet) prior to AOM treatment. SJW diet was found to significantly improve the overall survival of AOM-treated mice. Pre-treatment with the SJW diet significantly reduced body weight loss as well as decrease of serum albumin and cholesterol levels associated with AOM-induced colorectal tumorigenesis. SJW diet-fed mice showed a significant decrease in tumor multiplicity along with a decrease in incidence of large tumors and a trend towards decreased total tumor volume in a dose-dependent manner. A short-term study, which examined the effect of SJW prior to rectal bleeding, also showed a decrease in colorectal polyps in SJW diet-fed mice. NF-kB and extracellular signal-regulated kinase (ERK 1/2) pathways were attenuated by SJW administration. SJW extract resulted in early and continuous attenuation of these pathways in the colon epithelium of SJW diet-fed mice under both short term and long term treatment regimens. In conclusion, this study demonstrated the chemopreventive potential of SJW extract against colorectal cancer through attenuation of pro-inflammatory processes. Modulation of Colon Cancer by the Spice Nutmeg: Nutmeg, the seed of the fruit of Myristica fragrans, shows therapeutic efficacy in gastrointestinal disorders, and is a widely used agent for the treatment of stomach ailments in China. Nutmeg is known to exhibit antimicrobial activity against the phylum Proteobacteria, especially in Helicobacter pylori and Escherichia coli. Nutmeg can protect against dextran sulfate sodium-induced colitis in mice. These observations suggested that nutmeg might prevent colon cancer via the modulation of inflammation, oxidants and gut microbiota. By UPLC-ESI-QTOFMS-based metabolomics, this study revealed the accumulation of four uremic toxins (cresol sulfate, cresol glucuronide, indoxyl sulfate, and phenyl sulfate) in the serum of mice harboring adenomatous polyposis coli (APC) gene mutation-induced colon cancer. These uremic toxins, likely generated from the gut microbiota, were associated with increased expression of the proinflammatory cytokine IL-6 and a disorder of lipid metabolism. Nutmeg, that exhibits antimicrobial activity, attenuated the levels of uremic toxins and decreased intestinal tumorigenesis in Apcmin/+ mice. Nutmeg-treated Apcmin/+ mice had decreased IL-6 levels and normalized dysregulated lipid metabolism, suggesting that uremic toxins are responsible in part for the metabolic disorders that occur during tumorigenesis. These studies demonstrate a potential biochemical link between gut microbial metabolism, inflammation and metabolic disorders, and suggest that modulation of the gut microbiota and lipid metabolism using dietary intervention or drugs may be effective colon cancer chemoprevention strategies. N-methylnicotinamide and nicotinamide N-methyltransferase are associated with microRNA-1291-altered pancreatic carcinoma cell metabolome and suppressed tumorigenesis: The cell metabolome comprises abundant information that may be predictive of cell functions in response to epigenetic or genetic changes at different stages of cell proliferation and metastasis. An unbiased ultra-performance liquid chromatography-mass spectrometry-based metabolomics study revealed a significantly altered metabolome for human pancreatic carcinoma PANC-1 cells with gain-of-function non-coding microRNA-1291 (miR-1291), which led to a lower migration and invasion capacity as well as suppressed tumorigenesis in a xenograft tumor mouse model. A number of metabolites, including N-methylnicotinamide, involved in nicotinamide metabolism, and l-carnitine, isobutyryl-carnitine and isovaleryl-carnitine, involved in fatty acid metabolism, were elevated in miR-1291-expressing PANC-1. Notably, N-methylnicotinamide was elevated to the greatest extent, and this was associated with a sharp increase in nicotinamide N-methyltransferase (NNMT) mRNA level in miR-1291-expressing PANC-1 cells. In addition, expression of NNMT mRNA was inversely correlated with pancreatic tumor size in the xenograft mouse model. These results indicate that miR-1291-altered PANC-1 cell function is associated with the increase in N-methylnicotinamide level and NNMT expression, and in turn NNMT may be indicative of the extent of pancreatic carcinogenesis. Metabolic profiling of praziquantel enantiomers: Praziquantel (PZQ), prescribed as a racemic mixture, is the most readily available drug to treat schistosomiasis. In the present study, ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS) based metabolomics was employed to decipher the metabolic pathways and enantioselective metabolic differences of PZQ. Many phase I and four new phase II metabolites were found in urine and feces samples of mice 24h after dosing, indicating that the major metabolic reactions encompassed oxidation, dehydrogenation, and glucuronidation. Differences in the formation of all these metabolites were observed between (R)-PZQ and (S)-PZQ. In an in vitro phase I incubation system, the major involvement of CYP3A, CYP2C9, and CYP2C19 in the metabolism of PZQ, and CYP3A, CYP2C9, and CYP2C19 exhibited different catalytic activity toward the PZQ enantiomers. Apparent Km and Vmax differences were observed in the catalytic formation of three mono-oxidized metabolites by CYP2C9 and CYP3A4 further supporting the metabolic differences for PZQ enantiomers. Molecular docking showed that chirality resulted in differences in substrate location and conformation, which likely accounts for the metabolic differences. In conclusion, in silico, in vitro, and in vivo methods revealed the enantioselective metabolic profile of praziquantel.

Related projects