RESUMEN

SCOPE: Evidence suggests that the dietary consumption of plant extracts containing polyphenols might help prevent the onset of cancers of the gastrointestinal tract. In the present study, the chemopreventive and antiproliferative efficacy of a grapevine shoot extract (Vineatrol®30) containing resveratrol and resveratrol oligomers is investigated in vivo and in vitro. METHODS AND RESULTS: The in vivo study is performed using ApcMin mice on a high-fat diet, which represents a model of human adenomatous polyposis, while the potential of the extract as well as some of its isolated constituents to inhibit intestinal adenoma cell proliferation in vitro is investigated using APC10.1 cells derived from an ApcMin mouse. Vineatrol®30 at a low (2.3 mg kg-1  diet) or high dose (476 mg kg-1  diet) reduces the adenoma number in male and adenoma volume in female animals. Furthermore, Vineatrol®30 as well as resveratrol and two resveratrol tetramers compromise the expansion of APC10.1 cells by reducing cell number, inducing cell cycle arrest, cellular senescence, and apoptosis. However, except for the extract, none of the isolated resveratrol oligomers is more efficacious than resveratrol in these cells. CONCLUSION: Vineatrol®30 may merit further investigation as a potential dietary gastrointestinal cancer chemopreventive agent in humans.

Asunto(s)

Adenoma/prevención & control , Anticarcinógenos/farmacología , Neoplasias Intestinales/prevención & control , Fenoles/farmacología , Resveratrol/farmacología , Adenoma/metabolismo , Adenoma/patología , Animales , Anticarcinógenos/química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Caspasas/metabolismo , Proliferación Celular/efectos de los fármacos , Femenino , Neoplasias Intestinales/metabolismo , Neoplasias Intestinales/patología , Masculino , Ratones Mutantes , Fenoles/química , Resveratrol/química , Estilbenos/farmacología

RESUMEN

Resveratrol is widely promoted as a potential cancer chemopreventive agent, but a lack of information on the optimal dose prohibits rationally designed trials to assess efficacy. To challenge the assumption that "more is better," we compared the pharmacokinetics and activity of a dietary dose with an intake 200 times higher. The dose-response relationship for concentrations generated and the metabolite profile of [(14)C]-resveratrol in colorectal tissue of cancer patients helped us to define clinically achievable levels. In Apc(Min) mice (a model of colorectal carcinogenesis) that received a high-fat diet, the low resveratrol dose suppressed intestinal adenoma development more potently than did the higher dose. Efficacy correlated with activation of adenosine monophosphate-activated protein kinase (AMPK) and increased expression of the senescence marker p21. Nonlinear dose responses were observed for AMPK and mechanistic target of rapamycin (mTOR) signaling in mouse adenoma cells, culminating in autophagy and senescence. In human colorectal tissues exposed to low dietary concentrations of resveratrol ex vivo, we measured enhanced AMPK phosphorylation and autophagy. The expression of the cytoprotective NAD(P)H dehydrogenase, quinone 1 (NQO1) enzyme was also increased in tissues from cancer patients participating in our [(14)C]-resveratrol trial. These findings warrant a revision of developmental strategies for diet-derived agents designed to achieve cancer chemoprevention.

Asunto(s)

Adenoma/tratamiento farmacológico , Antineoplásicos Fitogénicos/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Estilbenos/administración & dosificación , Proteínas Quinasas Activadas por AMP/metabolismo , Adenoma/metabolismo , Adenoma/patología , Animales , Autofagia/efectos de los fármacos , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Dieta Alta en Grasa , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Resveratrol , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo

RESUMEN

SCOPE: There is strong epidemiological evidence indicating that consumption by humans of whole-grain foods including rice bran may be associated with a low incidence of cancer, especially in the colorectum. Molecular processes associated with cancer development may be retarded by fiber consumption. Consequently, intervention with dietary fiber might be suitable as a cancer chemoprevention strategy in high-risk populations. Here, we searched for putative molecular mechanism-based efficacy biomarkers of rice fiber consumption in the plasma of mice characterized by a genetic propensity to develop gastrointestinal adenomas. The hypothesis was tested that metabolic and proteomic changes in blood reflect the chemopreventive activity of rice bran. METHODS AND RESULTS: Apc(Min) mice received diet supplemented with rice bran at 5, 15, and 30%. Blood and tissue samples were taken. Plasma was subjected to MS-based proteomic and metabolic profiling analyses as well as assessment of hematocrit values. Gastrointestinal tracts were removed and adenomas were counted and their size was measured so that total tumor burden could be calculated. The hypothesis was tested that metabolic and proteomic changes in blood reflect chemopreventive activity. CONCLUSION: Rice bran consumption reduced adenoma burden and number in a dose-related fashion when compared to controls. Metabolic profiling data demonstrated strong clustering of the groups indicating that metabolic pathways are perturbed. Proteomic analysis identified adiponectin as a molecule that was significantly altered, which may play a role in tumor suppression.

Asunto(s)

Biomarcadores de Tumor/sangre , Neoplasias Colorrectales/dietoterapia , Fibras de la Dieta/administración & dosificación , Metabolómica , Proteómica , Adenoma/dietoterapia , Adenoma/patología , Animales , Neoplasias Colorrectales/patología , Dieta/veterinaria , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ratones , Oryza/química , Granos Enteros/química

RESUMEN

PURPOSE: TMFol (3',4',5'-trimethoxyflavonol) is a synthetic analogue of the naturally occurring flavonol fisetin and quercetin, which have been considered of potential usefulness in the management of prostate cancer. We investigated whether TMFol may have preclinical features superior to those of its two flavonol congeners. METHODS: The ability of the three flavonols to compromise prostate cancer cell survival was tested in four prostate cancer cell types 22Rv1, TRAMP C2, PC-3 and LNCaP. The effect of TMFol on prostate cancer development in vivo was investigated in nude mice bearing the 22Rv1 or TRAMP C2 tumours. RESULTS: TMFol inhibited cell growth in vitro in all four prostate cancer cell types more potently than fisetin and quercetin. It also interfered with TRAMP C2 tumour development in vivo, while fisetin and quercetin at equivalent doses were without activity in this model. Likewise, TMFol slowed the growth of the 22Rv1 tumour in vivo. Efficacy in either model was accompanied by induction of apoptosis, although in vitro only TRAMP C2 cells, but not 22Rv1, underwent apoptosis when exposed to TMFol. CONCLUSIONS: The results support the notion that among the three congeneric flavonols, quercetin, fisetin and TMFol, the latter may be the most suitable candidate agent for potential development in prostate cancer management.

Asunto(s)

Flavonoles/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Humanos , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Neoplasias de la Próstata/patología , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

The phytochemical resveratrol has been shown to exert numerous health benefits in preclinical studies, but its rapid metabolism and resulting poor bioavailability may limit translation of these effects to humans. Resveratrol metabolites might contribute to in vivo activity through regeneration of the parent compound. We present quantitation of sulfate and glucuronide conjugates of resveratrol in human plasma and tissue after repeated ingestion of resveratrol by volunteers and cancer patients, respectively. Subsequent pharmacokinetic characterization of a mixture of resveratrol-3-O-sulfate and resveratrol-4'-O-sulfate in mice showed that these metabolites are absorbed orally but have low bioavailabilities of ~14 and 3%, respectively. Sulfate hydrolysis in vivo liberated free resveratrol, which accounted for ~2% of the total resveratrol species present in mouse plasma. Monosulfate metabolites were also converted to the parent in human colorectal cells. The extent of cellular uptake was dependent on specific membrane transporters and dictated antiproliferative activity. Sulfate metabolites induced autophagy and senescence in human cancer cells; these effects were abrogated by inclusion of a sulfatase inhibitor, which reduced intracellular resveratrol. Together, our findings suggest that resveratrol is delivered to target tissues in a stable sulfate-conjugated form and that the parent compound is gradually regenerated in selected cells and may give rise to the beneficial effects in vivo. At doses considered to be safe in humans, resveratrol generated via this route may be of greater importance than the unmetabolized form.

Asunto(s)

Autofagia , Senescencia Celular , Espacio Intracelular/metabolismo , Estilbenos/metabolismo , Sulfatos/metabolismo , Animales , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular , Senescencia Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Neoplasias Colorrectales/sangre , Glucurónidos/sangre , Humanos , Espacio Intracelular/efectos de los fármacos , Proteínas de Transporte de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Resveratrol , Estilbenos/sangre , Estilbenos/farmacología

RESUMEN

Curcumin, the main constituent of turmeric, is suspected to possess cancer chemopreventive properties. Pharmacokinetic and pharmacodynamic parameters have been reported, but few data exist describing whether methodologies are suitably robust for curcuminoid detection in colonic biopsy specimens. Information on the acceptability of prolonged administration of daily curcumin is not available. This is of vital importance to implement chemoprevention strategies. This study aimed to quantify levels of curcuminoids in colorectal mucosa of patients undergoing colorectal endoscopy or surgical resection and to obtain information on the acceptability and compliance with daily curcumin. Curcumin C3 complex (2.35 g) was administered to patients once daily for 14 days before endoscopic biopsy or colonic resection. Safety and tolerance were monitored. Analysis of curcuminoids in plasma, urine, and colonic mucosa was conducted by ultraperformance liquid chromatography (UPLC)-UV with characterization by liquid chromatography/tandem mass spectrometry (LC/MS-MS). Twenty-four of 26 patients commencing curcumin completed the course. Six patients reported mild gastrointestinal adverse events. Curcuminoids were detectable in nine of 24 plasma samples, 24 of 24 urine samples, and in the colonic mucosa of all 23 biopsied participants. Mean tissue levels were 48.4 µg/g (127.8 nmol/g) of parent curcuminoids. The major conjugate, curcumin glucuronide, was detectable in 29 of 35 biopsies. High levels of topical curcumin persisted in the mucosa for up to 40 hours postadministration. Sixteen participants (67%) stated that they would take curcumin long-term should it be of proven benefit. In summary, pharmacologically active levels of curcumin were recovered from colonic mucosa. The regimen used here seems safe, and patients support its use in long-term trials.

Asunto(s)

Antineoplásicos Fitogénicos/farmacología , Carcinoma/tratamiento farmacológico , Colon/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Curcumina/farmacocinética , Aceptación de la Atención de Salud , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/efectos adversos , Disponibilidad Biológica , Carcinoma/metabolismo , Carcinoma/patología , Carcinoma/orina , Colon/efectos de los fármacos , Colon/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/orina , Curcumina/administración & dosificación , Curcumina/efectos adversos , Femenino , Humanos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Mucosa Intestinal/fisiopatología , Masculino , Persona de Mediana Edad , Aceptación de la Atención de Salud/estadística & datos numéricos , Cooperación del Paciente/estadística & datos numéricos , Proyectos Piloto , Factores de Tiempo

Asunto(s)

Antineoplásicos Fitogénicos/farmacocinética , Curcumina/farmacocinética , Nanopartículas , Femenino , Humanos , Masculino

RESUMEN

SCOPE: Rosmarinic acid (RA), a constituent of culinary herbs is considered to possess cancer chemopreventive properties. It has been shown to inhibit the development of cancer in preclinical models but data are conflicting and whether it can protect against gastrointestinal malignancies in vivo has not been examined. This study aimed to investigate the effect of RA on the development of intestinal adenomas in the Apc(Min) mouse model of colorectal carcinogenesis, and to correlate efficacy with levels of RA achieved in the plasma and gastrointestinal tract. METHODS AND RESULTS: RA inhibited the growth of APC10.1 cells derived from Apc(Min) mouse adenomas, with an IC50 of 43 µM. Consumption of dietary RA (0.3%) by Apc(Min) mice for 8 weeks post weaning decreased adenoma burden by ∼35%, but the difference from controls was not significant. Although RA significantly decreased the frequency of large adenomas, the number of small ones increased. Using a novel validated HPLC assay, average levels of RA in the plasma and intestinal mucosa of these mice were found to be 1.1 µM and 38 nmol/g, respectively. CONCLUSION: Chronic consumption of RA furnished quantifiable levels of parent compound in the plasma and intestinal tract of Apc(Min) mice and may slow adenoma development.

Asunto(s)

Adenoma/prevención & control , Anticarcinógenos/farmacología , Cinamatos/farmacología , Neoplasias Colorrectales/prevención & control , Depsidos/farmacología , Adenoma/genética , Adenoma/patología , Animales , Calibración , Cromatografía Líquida de Alta Presión/métodos , Cinamatos/análisis , Cinamatos/farmacocinética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Depsidos/análisis , Depsidos/farmacocinética , Suplementos Dietéticos , Modelos Animales de Enfermedad , Ensayos de Selección de Medicamentos Antitumorales , Genes APC , Mucosa Intestinal/efectos de los fármacos , Neoplasias Intestinales/genética , Neoplasias Intestinales/patología , Neoplasias Intestinales/prevención & control , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Células Tumorales Cultivadas , Ácido Rosmarínico

RESUMEN

3',4',5'-Trimethoxyflavonol (TMFol) is a synthetic flavonol with preclinical cancer chemopreventive properties. The hypothesis was tested that, in mice, p.o. administration of TMFol results in measureable levels of the parent in target tissues. A single oral dose (240 mg/kg) was administered to mice (n = 4 per time point) with time points ranging from 5 to 1440 min. TMFol and its metabolites were identified and quantitated in all tissues by high-performance liquid chromatography (HPLC). Plasma levels of TMFol were at the limit of quantification or below, although metabolites were identified. Peak levels of TMFol in the gastrointestinal tract and the prostate averaged 1671 ± 265 µg/g (5.3 µmol/g) and 6.0 ± 1.6 µg/g (18.4 nmol/g), and occurred 20 and 360 min post-dose, respectively. The area under the tissue concentration-time curve (AUC) for TMFol was greater than those of the metabolites, indicating that TMFol is relatively metabolically stable. Micromolar TMFol levels are easily achieved in the prostate and gastrointestinal tract, suggesting that TMFol might exert chemopreventive efficacy at these tissue sites. Further investigations are warranted to elucidate the potential chemopreventive potency of TMFol.

Asunto(s)

Anticarcinógenos/metabolismo , Anticarcinógenos/farmacocinética , Flavonoles/metabolismo , Flavonoles/farmacocinética , Animales , Anticarcinógenos/análisis , Anticarcinógenos/química , Cromatografía Líquida de Alta Presión/métodos , Femenino , Flavonoides/análisis , Flavonoides/química , Flavonoides/metabolismo , Flavonoides/farmacocinética , Flavonoles/análisis , Flavonoles/química , Mucosa Intestinal/química , Mucosa Intestinal/metabolismo , Hígado/metabolismo , Masculino , Redes y Vías Metabólicas , Ratones , Ratones Endogámicos C57BL , Sensibilidad y Especificidad , Distribución Tisular

RESUMEN

There is now robust preclinical evidence to suggest that resveratrol possesses cancer chemopreventive properties. A series of clinical pilot studies has provided insights into its pharmacokinetics, and data on its human antineoplastic pharmacodynamics start to emerge. It is likely that resveratrol will be developed further in the clinic as a putative cancer chemopreventive agent. The question that remains unresolved is: What is the most suitable dose of resveratrol for effective cancer preventive intervention? Mechanistic studies in cells in vitro have almost invariably used concentrations of resveratrol in the 10(-5) to 10(-4) M range, which is much higher than those which can be achieved in the human biophase after consumption of doses up to 1 g. Many of the preclinical efficacy studies in rodent models of carcinogenesis have employed doses which are dramatically above those which can be ingested with the diet. New experimental paradigms need to be used to obtain information on pharmacological changes elicited by resveratrol when present at very low concentrations or when administered at dietary-relevant doses.

Asunto(s)

Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias/prevención & control , Estilbenos/administración & dosificación , Estilbenos/uso terapéutico , Animales , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Humanos , Resveratrol

RESUMEN

The patterns and levels of urinary excreted ribonucleosides which reflect RNA turnover and metabolism in humans offer the potential for early detection of disease and monitoring of therapeutic intervention. A liquid chromatography/tandem mass spectrometry (LC/MS/MS) method employing constant neutral loss (CNL) scanning for the loss of the ribose moiety (132 u) was used to detect ribonucleosides in human urine and to evaluate this analytical platform for biomarker research in clinical trials. Ribonucleosides were stable and not influenced by the time spent at room temperature prior to freezing or long-term storage at -80 °C. Matrix effects caused variation in the mass spectrometer response which was dependent on the concentration of the analysed urine sample. For the use of urinary ribonucleoside profiling in clinical biomarker studies, adjustment of the urine samples to a common concentration prior to sample preparation is therefore advocated. Changes in the mass spectrometer response should be accounted for by the use of an internal standard added after sample preparation. Diurnal variation exceeded inter-day variation of an individual's ribonucleoside profile, but inter-person differences were predominant and allowed the separation of individuals against each other in a multivariate space. Due to considerable diurnal variation the use of spot urine samples would introduce unnecessary variation and should be replaced by the collection of multiple spot urine samples across the day, where possible. Should such a protocol not be feasible, biological intra-day and inter-day variation must be considered and accounted for in the data interpretation.

Asunto(s)

Cromatografía Liquida/métodos , Ribonucleósidos/orina , Espectrometría de Masas en Tándem/métodos , Adulto , Biomarcadores/química , Biomarcadores/orina , Ácidos Borónicos/química , Humanos , Persona de Mediana Edad , Análisis de Componente Principal , Reproducibilidad de los Resultados , Ribonucleósidos/química , Extracción en Fase Sólida , Temperatura

RESUMEN

SCOPE: The effect of two anthocyanin-rich berry extracts (A, bilberry; B, red grape) on topoisomerases was investigated in a cell-free system and in human HT29 colon carcinoma cells. In parallel, their impact on DNA integrity was determined. METHODS AND RESULTS: The berry extracts suppressed the activity of topoisomerase I at concentrations ≥50 µg/mL. The activity of the topoisomerase II isoform was preferentially diminished (≥1 µg/mL). Within HT29 cells, the extracts were found to act as catalytic inhibitors without stabilizing the cleavable complex. Although topoisomerase activity was inhibited, none of the extracts induced DNA strand breaks up to 50 µg/mL. Moreover, pre- and coincubation of HT29 cells with A (≥1 µg/mL) significantly suppressed (p-value ≤0.001) the strand-breaking effects of camptothecin, whereas B was found to be less effective (1 µg/mL; p-value ≤0.05). Both extracts were found to significantly diminish doxorubicin-mediated DNA strand breaks at concentrations ≥1 µg/mL (p-value ≤0.001). Consistent with these results, the extracts suppressed doxorubicin-mediated enhancement of levels of topoisomerase II covalently linked to DNA in HT29 cells. CONCLUSION: These results raise the possibility that high intake of berry extracts may protect DNA and thus counteract the therapeutic effectiveness of orally applied topoisomerase poisons during chemotherapy.

Asunto(s)

Antocianinas/farmacología , Antineoplásicos Fitogénicos/farmacología , Daño del ADN/efectos de los fármacos , ADN-Topoisomerasas de Tipo II/metabolismo , ADN-Topoisomerasas de Tipo I/metabolismo , Extractos Vegetales/farmacología , Camptotecina/farmacología , Sistema Libre de Células , Neoplasias del Colon/tratamiento farmacológico , ADN/efectos de los fármacos , ADN/metabolismo , Doxorrubicina/farmacología , Células HT29 , Humanos , Vaccinium myrtillus/química

RESUMEN

An expanding body of preclinical evidence suggests resveratrol has the potential to impact a variety of human diseases. To translate encouraging experimental findings into human benefits, information is first needed on the safety, pharmacokinetics, pharmacodynamics, and, ultimately, clinical efficacy of resveratrol. Published clinical trials have largely focused on characterizing the pharmacokinetics and metabolism of resveratrol. Recent studies have also evaluated safety and potential mechanisms of activity following multiple dosing, and have found resveratrol to be safe and reasonably well-tolerated at doses of up to 5 g/day. However, the occurrence of mild to moderate side effects is likely to limit the doses employed in future trials to significantly less than this amount. This review describes the available clinical data, outlines how it supports the continuing development of resveratrol, and suggests what additional information is needed to increase the chances of success in future clinical trials.

Asunto(s)

Ensayos Clínicos como Asunto/métodos , Estilbenos/farmacocinética , Estilbenos/uso terapéutico , Animales , Ensayos Clínicos como Asunto/tendencias , Humanos , Resveratrol

RESUMEN

Anthocyanins possess cancer chemopreventive properties in preclinical models. Their clinical pharmacology is only poorly understood. In this pilot study, anthocyanins and their metabolites were analysed in the urine of two patients with colorectal liver metastases. They received a single dose of 1.88 g standardized bilberry extract (mirtoselect) via either nasogastric or nasojejunal tube intra-operatively during liver resection. HPLC-MS/MS and HPLC-UV analysis showed there were more anthocyanins and metabolites in the urine of the patient who received mirtoselect via the stomach than via the jejunum. This result is consistent with information obtained in rodents which suggests the stomach is the predominant site for anthocyanin absorption.

Asunto(s)

Antocianinas/orina , Neoplasias Colorrectales/orina , Neoplasias Hepáticas/orina , Extractos Vegetales/administración & dosificación , Vaccinium myrtillus/química , Anciano , Antocianinas/química , Antocianinas/aislamiento & purificación , Antineoplásicos/administración & dosificación , Cromatografía Líquida de Alta Presión , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Humanos , Intubación Gastrointestinal , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/cirugía , Masculino , Proyectos Piloto , Espectrometría de Masas en Tándem

RESUMEN

PURPOSE: The flavones tricin (4',5,7-trihydroxy-3',5'-dimethoxyflavone) and 3',4',5',5,7-pentamethoxyflavone (PMF) are under development as potential colorectal cancer chemopreventive agents as they reduced adenoma development in the Apc(Min) mouse model of intestinal carcinogenesis. Here, the pharmacokinetic properties and metabolism of these flavones after oral administration were compared in mice. METHODS: C57BL/6 J mice received an oral bolus of PMF or tricin (807 µmol/kg). Parent flavone and metabolites were analyzed by HPLC/UV in plasma, liver and gastrointestinal tissues. Flavones were incubated with mouse or human hepatic microsomes or 9000xg supernatant (S9), both fortified with a NADPH-generating system and either uridine 5'-diphosphoglucuronic acid (UDPGA, microsomes) or 3'-phosphoadenosine-5'-phosphosulfate (PAPS, S9). Disappearance of substrate was assessed by HPLC/UV, metabolites were characterized by HPLC/MS/MS. RESULTS: Plasma concentrations and area under the plasma concentration versus time curve for PMF were higher than those for tricin. A mono-O-desmethyl PMF and several isomeric mono-O-desmethyl PMF glucuronides and sulfonates were major PMF metabolites in murine plasma, liver and intestinal tissue. In murine and human liver fractions, in vitro metabolic removal of tricin was faster than that of PMF. On kinetic analysis of metabolite generation in these incubations, apparent maximal velocity (V(max)) values for the generation of tricin O-glucuronide or O-sulfonate were consistently several fold higher than those characterizing the production of mono-O-desmethyl PMF glucuronides or sulfonates via the intermediacy of O-desmethyl PMF. CONCLUSIONS: The results suggest that inclusion of methoxy moieties confers metabolic stability onto the flavone scaffold.

Asunto(s)

Citosol/metabolismo , Flavonoides/metabolismo , Flavonoides/farmacocinética , Microsomas Hepáticos/metabolismo , Adulto , Animales , Área Bajo la Curva , Arilsulfonatos/metabolismo , Biocatálisis , Sangre/metabolismo , Femenino , Flavonas/metabolismo , Flavonoides/administración & dosificación , Flavonoides/sangre , Glucuronatos/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Cinética , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Adulto Joven

RESUMEN

Resveratrol, a naturally occurring polyphenol, has cancer chemopreventive properties in preclinical models. It has been shown to downregulate the levels of insulin-like growth factor-1 (IGF-I) in rodents. The purpose of the study was to assess its safety, pharmacokinetics, and effects on circulating levels of IGF-I and IGF-binding protein-3 (IGFBP-3) after repeated dosing. Forty healthy volunteers ingested resveratrol at 0.5, 1.0, 2.5, or 5.0 g daily for 29 days. Levels of resveratrol and its metabolites were measured by high performance liquid chromatography-UV in plasma obtained before and up to 24 hours after a dose between days 21 and 28. IGF-I and IGFBP-3 were measured by ELISA in plasma taken predosing and on day 29. Resveratrol was safe, but the 2.5 and 5 g doses caused mild to moderate gastrointestinal symptoms. Resveratrol-3-O-sulfate, resveratrol-4'-O-glucuronide, and resveratrol-3-O-glucuronide were major plasma metabolites. Maximal plasma levels and areas under the concentration versus time curve for the metabolites dramatically exceeded those for resveratrol, in the case of areas under the concentration versus time curve, by up to 20.3-fold. Compared with predosing values, the ingestion of resveratrol caused a decrease in circulating IGF-I and IGFBP-3 (P<0.04 for both), respectively, in all volunteers. The decrease was most marked at the 2.5 g dose level. The results suggest that repeated administration of high doses of resveratrol generates micromolar concentrations of parent and much higher levels of glucuronide and sulfate conjugates in the plasma. The observed decrease in circulating IGF-I and IGFBP-3 might contribute to cancer chemopreventive activity.

Asunto(s)

Antineoplásicos Fitogénicos/farmacocinética , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/metabolismo , Estilbenos/farmacocinética , Dolor Abdominal/inducido químicamente , Adulto , Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/metabolismo , Área Bajo la Curva , Cromatografía Líquida de Alta Presión , Diarrea/inducido químicamente , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Glucurónidos/sangre , Glucurónidos/metabolismo , Humanos , Tasa de Depuración Metabólica , Persona de Mediana Edad , Náusea/inducido químicamente , Resveratrol , Estilbenos/efectos adversos , Estilbenos/sangre , Estilbenos/metabolismo , Adulto Joven

RESUMEN

Resveratrol is a phytochemical with chemopreventive activity in preclinical rodent models of colorectal carcinogenesis. Antiproliferation is one of the many chemopreventive modes of action it has been shown to engage in. Concentrations of resveratrol, which can be achieved in human tissues after p.o. administration, have not yet been defined. The purpose of this study was to measure concentrations of resveratrol and its metabolites in the colorectal tissue of humans who ingested resveratrol. Twenty patients with histologically confirmed colorectal cancer consumed eight daily doses of resveratrol at 0.5 or 1.0 g before surgical resection. Resveratrol was found to be well tolerated. Normal and malignant biopsy tissue samples were obtained before dosing. Parent compound plus its metabolites resveratrol-3-O-glucuronide, resveratrol-4'-O-glucuronide, resveratrol-3-O-sulfate, resveratrol-4'-O-sulfate, resveratrol sulfate glucuronide, and resveratrol disulfate were identified by high-performance liquid chromatography (HPLC) with UV or mass spectrometric detection in colorectal resection tissue. Quantitation was achieved by HPLC/UV. Cell proliferation, as reflected by Ki-67 staining, was compared in preintervention and postintervention tissue samples. Resveratrol and resveratrol-3-O-glucuronide were recovered from tissues at maximal mean concentrations of 674 and 86.0 nmol/g, respectively. Levels of resveratrol and its metabolites were consistently higher in tissues originating in the right side of the colon compared with the left. Consumption of resveratrol reduced tumor cell proliferation by 5% (P = 0.05). The results suggest that daily p.o. doses of resveratrol at 0.5 or 1.0 g produce levels in the human gastrointestinal tract of an order of magnitude sufficient to elicit anticarcinogenic effects. Resveratrol merits further clinical evaluation as a potential colorectal cancer chemopreventive agent.

Asunto(s)

Adenocarcinoma/tratamiento farmacológico , Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Estilbenos/uso terapéutico , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Anciano , Anciano de 80 o más Años , Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/farmacocinética , Procesos de Crecimiento Celular/efectos de los fármacos , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Terapia Combinada , Femenino , Humanos , Inmunohistoquímica , Antígeno Ki-67/metabolismo , Masculino , Persona de Mediana Edad , Resveratrol , Estilbenos/efectos adversos , Estilbenos/farmacocinética

RESUMEN

Some naturally occurring flavonols, exemplified by quercetin, seem to possess experimental cancer chemopreventive efficacy. Modulation of p53 is a mechanism thought to contribute to their activity. The hypothesis was tested that a synthetic flavonol, 3',4',5'-trimethoxyflavonol (TMFol), can interfere with tumor development and p53 expression in two models of colorectal carcinogenesis, Apc(Min) mice and human-derived HCT116 adenocarcinoma-bearing nude mice. Mice received TMFol with their diet (0.2%) from weaning to week 16 in the case of Apc(Min) or from either day 7 before ("TMFol early") or day 7 after ("TMFol late") tumor inoculation in HCT116 mice. The ability of TMFol to affect tumor proliferation or apoptosis, as reflected by staining for Ki-67 or cleaved caspase-3, respectively, was studied in HCT116 tumors. TMFol tumor levels were measured by high-performance liquid chromatography. Consumption of TMFol reduced small intestinal adenoma burden in Apc(Min) mice by 47%, compared with control mice (P < 0.002). The TMFol early regimen approximately halved HCT116 tumor size (P < 0.05), decreased tumor proliferation, and increased apoptosis, whereas the TMFol late regimen had no significant effect when compared with controls. In tumor tissues from mice, in which TMFol reduced tumor development, p53 expression was increased 3-fold in Apc(Min) and 1.5-fold in HCT116 tumor-bearing mice (P = 0.02). TMFol increased p53 also in cells derived from these tumors. TMFol was detected in HCT116 tumors, but levels did not correlate with tumor burden. TMFol was not mutagenic in the Ames test. The results suggest that chemical modification of the flavonol structure may generate safe and efficacious cancer chemopreventive agents.

Asunto(s)

Carcinoma/prevención & control , Neoplasias Colorrectales/prevención & control , Resistencia a Antineoplásicos/genética , Flavonoides/uso terapéutico , Genes p53/fisiología , Animales , Antineoplásicos Fitogénicos/uso terapéutico , Carcinoma/genética , Quimioprevención , Neoplasias Colorrectales/genética , Evaluación Preclínica de Medicamentos , Células HCT116 , Humanos , Ratones , Ratones Desnudos , Ratones Transgénicos , Quercetina/análogos & derivados , Resultado del Tratamiento , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Green tea polyphenols (GTP) have been widely investigated for their potential to prevent prostate cancer. However, results from epidemiological and clinical studies are equivocal. Studies in the TRAMP (TRansgenic Adenocarcinoma of the Mouse Prostate) mouse suggest that the chemopreventive efficacy of GTP is higher in young animals with early stages of carcinogenesis than in old ones. Here, effects of GTP on prostate carcinogenesis in TRAMP mice were assessed by comparing pathological changes with (1)H-NMR metabolic profiling of plasma and extracts of prostate tissue. Mice received 0.05% GTP in their drinking water for 4 or 25 weeks after weaning. Age-matched wild-type mice were included in the study in order to establish differences in GTP effects between normal and TRAMP mice. Dietary GTP did not markedly alter prostate carcinogenesis as reflected by pathology and prostate tissue metabolic profile. However, a systemic effect of GTP consumption was observed in young mice, regardless of genotype. Plasma lipid signals were decreased in 8 week old mice which received GTP compared to age-matched controls by 19, 61, 27, 34 and 15% (p

Asunto(s)

Adenocarcinoma/patología , Flavonoides/farmacología , Fenoles/farmacología , Neoplasias de la Próstata/patología , Té/química , Adenocarcinoma/sangre , Animales , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Polifenoles , Neoplasias de la Próstata/sangre

RESUMEN

PURPOSE: Red grape pomace extract (oenocyanin) is a cheap and rich source of anthocyanins, the agents suggested to possess cancer chemopreventive properties. Here the hypothesis was tested that oenocyanin added to the diet can interfere with intestinal adenoma development in the Apc(Min) mouse, a model of intestinal carcinogenesis linked to an Apc mutation. METHODS: Mice received oenocyanin (0.3%) in their diet until week 16, when adenoma number and burden were recorded. Expression of Akt and ERK proteins was studied by Western blot in adenomas to discover effects of anthocyanins on cellular signalling via the PI3 and MAP kinase pathways. Levels of anthocyanins were measured by HPLC with visible spectroscopic or mass spectrometric detection. RESULTS: In mice which had consumed oenocyanin, overall adenoma burden was halved and adenoma number was marginally reduced when compared with mice on control diet. The proliferation index in colonic adenomatous crypts, as reflected by Ki-67 staining, was significantly decreased from 88.14% in control mice to 75.6+/-4% in mice on oenocyanin (P=0.014). Expression of Akt in small intestinal adenomas from Apc(Min) mice on oenocyanin was reduced by 54% (P=0.003), when compared to controls. Oenocyanin anthocyanins and glucuronide metabolites were found in the urine and intestine but not in plasma. CONCLUSIONS: The results suggest that oenocyanin may be a viable and economical alternative to anthocyanin-rich berry extracts for chemopreventive intervention. Akt and pErk might be suitable biomarkers of anthocyanin target organ efficacy.

Asunto(s)

Adenoma/prevención & control , Antocianinas/análisis , Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias Intestinales/prevención & control , Fitoterapia/métodos , Vitis/química , Adenoma/metabolismo , Adenoma/patología , Animales , Antocianinas/farmacocinética , Biomarcadores de Tumor/metabolismo , Proliferación Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión/métodos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos/métodos , Mucosa Intestinal/metabolismo , Neoplasias Intestinales/metabolismo , Neoplasias Intestinales/patología , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/metabolismo , eIF-2 Quinasa/metabolismo