3-8-dihydroxy-6h-dibenzo(b-d)pyran-6-one and Colorectal-Neoplasms

Urolithins are bioactive metabolites produced by the gut microbiota from ellagitannins (ETs) and ellagic acid (EA). We investigated whether urolithins could be detected in colon tissues from colorectal cancer (CRC) patients after pomegranate extract (PE) intake.. CRC patients (n = 52) were divided into controls and PEs consumers (900 mg/day for 15 days) before surgical resection. PEs with low (PE-1) and high (PE-2) punicalagin:EA ratio were administered. Twenty-three metabolites, but no ellagitannins, were detected in urine, plasma, normal (NT) or malignant (MT) colon tissues using UPLC-ESI-QTOF-MS/MS (UPLC, ultra performance liquid chromatography; QTOF, quadrupole TOF). Free EA, five EA conjugates, gallic acid and 12 urolithin derivatives were found in colon tissues. Individual and total metabolites levels were higher in NT than in MT, independently of the PE consumed. The maximal mean concentration (1671 ± 367 ng/g) was found in NT after consumption of PE-1 and the lowest concentration (42.4 ± 10.2 ng/g) in MT with PE-2. Urolithin A or isourolithin A were the main urolithins produced (54 and 46% patients with urolithin A or isourolithin A phenotype, respectively). High punicalagin content (PE-2) hampered urolithins formation.. Significant levels of EA derivatives and urolithins are found in human colon tissues from CRC patients after consumption of pomegranate. Further studies are warranted to elucidate their biological activity.

Topics: Adult; Aged; Aged, 80 and over; Body Mass Index; Chromatography, Liquid; Colon; Colorectal Neoplasms; Coumarins; Ellagic Acid; Female; Humans; Hydrolyzable Tannins; Limit of Detection; Lythraceae; Male; Metabolomics; Middle Aged; Plant Extracts; Polyphenols; Reproducibility of Results; Tandem Mass Spectrometry

To investigate the effect of pomegranate mesocarp, a polyphenol-rich by-product of juice production, in colorectal cancer (CRC) chemoprevention.. A mesocarp decoction (PMD) is administered for 6 weeks in the diet to Pirc rats, mutated in Apc, a key-gene in CRC. Mucin-depleted foci (MDFs), as CRC biomarkers, are reduced in PMD-fed rats compared to controls (MDF/colon: 34 ± 4 versus 47 ± 3, p = 0.02). There is an increase in apoptosis in MDFs from PMD-treated rats compared to controls (2.5 ± 0.2 versus 1.6 ± 0.2, p < 0.01). To elucidate the involved mechanisms, two colon-relevant metabolites of the polyphenolic and fiber PMD components, urolithin-A (u-A) and sodium butyrate (SB), are tested alone or in combination in vitro (colon cancer cells), and ex vivo in adenoma (AD) and normal mucosa (NM) from Pirc rats. u-A 25 μm plus SB 2.5 mm (USB) causes a significant reduction in COX-2 protein expression compared to untreated controls (about -70% in cancer cell cultures, AD, and NM), and a strong increase in C-CASP-3 expression in cells (about ten times), in AD and NM (+74 and +69%).. These data indicate a chemopreventive activity of PMD due, at least in part, to pro-apoptotic and anti-inflammatory action of its metabolites that could be exploited in high-risk patients.

Topics: Adenoma; Adenomatous Polyposis Coli Protein; Animals; Anticarcinogenic Agents; Apoptosis; Butyric Acid; Cell Proliferation; Colitis; Colonic Neoplasms; Colorectal Neoplasms; Coumarins; Gastric Mucosa; HCT116 Cells; HT29 Cells; Humans; Lythraceae; Rats, Inbred F344; Rats, Mutant Strains

Autophagy is an evolutionarily conserved pathway in which cytoplasmic contents are degraded and recycled. This study found that submicromolar concentrations of urolithin A, a major polyphenol metabolite, induced autophagy in SW620 colorectal cancer (CRC) cells. Exposure to urolithin A also dose-dependently decreased cell proliferation, delayed cell migration, and decreased matrix metalloproteinas-9 (MMP-9) activity. In addition, inhibition of autophagy by Atg5-siRNA, caspases by Z-VAD-FMK suppressed urolithin A-stimulated cell death and anti-metastatic effects. Micromolar urolithin A concentrations induced both autophagy and apoptosis. Urolithin A suppressed cell cycle progression and inhibited DNA synthesis. These results suggest that dietary consumption of urolithin A could induce autophagy and inhibit human CRC cell metastasis. Urolithins may thus contribute to CRC treatment and offer an alternative or adjunct chemotherapeutic agent to combat this disease.

Topics: Apoptosis; Autophagy; Caspases; Cell Line, Tumor; Cell Movement; Cell Proliferation; Colorectal Neoplasms; Coumarins; Humans; Hydrolyzable Tannins; Matrix Metalloproteinase 9; RNA, Small Interfering

Ellagitannins, ellagic acid, and the colonic metabolites urolithins (Uros) exhibit anticancer effects against colon cells, but a comprehensive molecular analysis has not been done. Herein, we used a panel of cell lines to first time evaluate the antiproliferative properties and accompanying molecular responses of two ellagitannin metabolites mixtures mimicking the situation in vivo and of each individual metabolite.. We examined cell growth, cell cycle, apoptosis, and the expression of related genes and microRNAs (miRs) in a panel of nonmalignant and malignant colon cell lines. Regardless of the composition, the mixed metabolites similarly inhibited proliferation, induced cycle arrest, and apoptosis. All the metabolites contributed to these effects, but Uro-A, isourolithin A, Uro-C, and Uro-D were more potent than Uro-B and ellagic acid. Despite molecular differences between the cell lines, we discerned relevant changes in key cancer markers and corroborated the induction of CDKN1A (cyclin-dependent kinase inhibitor 1A gene (p21, Cip1); encoding p21) as a common step underlying the anticancer properties of Uros. Interestingly, cell-unique downregulation of miR-224 or upregulation of miR-215 was found associated with CDKN1A induction.. Physiologically relevant mixtures of Uros exert anticancer effects against colon cancer cells via a common CDKN1A upregulatory mechanism. Other associated molecular responses are however heterogeneous and mostly cell-specific.

Topics: Anticarcinogenic Agents; Apoptosis; Cell Line; Cell Line, Tumor; Colon; Colonic Neoplasms; Colorectal Neoplasms; Coumarins; Cyclin-Dependent Kinase Inhibitor p21; Ellagic Acid; Gene Expression Regulation, Neoplastic; HT29 Cells; Humans; Hydrolyzable Tannins; MicroRNAs