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1.
Int J Mol Sci ; 25(2)2024 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-38255828

RESUMO

Resveratrol has long been proposed as being beneficial to human health across multiple morbidities, yet there is currently no conclusive clinical evidence to advocate its recommendation in any healthcare setting. A large cohort with high-quality clinical data and clearly defined biomarkers or endpoints are required to draw meaningful conclusions. This systematic review compiles every clinical trial conducted using a defined dose of resveratrol in a purified form across multiple morbidities to highlight the current 'state-of-play' and knowledge gaps, informing future trial designs to facilitate the realisation of resveratrol's potential benefits to human health. Over the last 20 years, there have been almost 200 studies evaluating resveratrol across at least 24 indications, including cancer, menopause symptoms, diabetes, metabolic syndrome, and cardiovascular disease. There are currently no consensus treatment regimens for any given condition or endpoint, beyond the fact that resveratrol is generally well-tolerated at a dose of up to 1 g/day. Additionally, resveratrol consistently reduces inflammatory markers and improves aspects of a dysregulated metabolism. In conclusion, over the last 20 years, the increasing weight of clinical evidence suggests resveratrol can benefit human health, but more large, high-quality clinical trials are required to transition this intriguing compound from health food shops to the clinic.


Assuntos
Doenças Cardiovasculares , Síndrome Metabólica , Feminino , Humanos , Resveratrol/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Consenso , Confiabilidade dos Dados
3.
bioRxiv ; 2023 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-38187560

RESUMO

Inhibition of Bruton's tyrosine kinase (BTK) has proven to be highly effective in the treatment of B-cell malignancies such as chronic lymphocytic leukemia (CLL), autoimmune disorders and multiple sclerosis. Since the approval of the first BTK inhibitor (BTKi), Ibrutinib, several other inhibitors including Acalabrutinib, Zanubrutinib, Tirabrutinib and Pirtobrutinib have been clinically approved. All are covalent active site inhibitors, with the exception of the reversible active site inhibitor Pirtobrutinib. The large number of available inhibitors for the BTK target creates challenges in choosing the most appropriate BTKi for treatment. Side-by-side comparisons in CLL have shown that different inhibitors may differ in their treatment efficacy. Moreover, the nature of the resistance mutations that arise in patients appears to depend on the specific BTKi administered. We have previously shown that Ibrutinib binding to the kinase active site causes unanticipated long-range effects on the global conformation of BTK (Joseph, R.E., et al., 2020, https://doi.org/10.7554/eLife.60470 ). Here we show that binding of each of the five approved BTKi to the kinase active site brings about distinct allosteric changes that alter the conformational equilibrium of full-length BTK. Additionally, we provide an explanation for the resistance mutation bias observed in CLL patients treated with different BTKi and characterize the mechanism of action of two common resistance mutations: BTK T474I and L528W.

4.
PLoS One ; 17(2): e0262364, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35130302

RESUMO

Research into the metabolism of the non-essential amino acid (NEAA) proline in cancer has gained traction in recent years. The last step in the proline biosynthesis pathway is catalyzed by pyrroline-5-carboxylate reductase (PYCR) enzymes. There are three PYCR enzymes: mitochondrial PYCR1 and 2 and cytosolic PYCR3 encoded by separate genes. The expression of the PYCR1 gene is increased in numerous malignancies and correlates with poor prognosis. PYCR1 expression sustains cancer cells' proliferation and survival and several mechanisms have been implicated to explain its oncogenic role. It has been suggested that the biosynthesis of proline is key to sustain protein synthesis, support mitochondrial function and nucleotide biosynthesis. However, the links between proline metabolism and cancer remain ill-defined and are likely to be tissue specific. Here we use a combination of human dataset, human tissue and mouse models to show that the expression levels of the proline biosynthesis enzymes are significantly increased during colorectal tumorigenesis. Functionally, the expression of mitochondrial PYCRs is necessary for cancer cells' survival and proliferation. However, the phenotypic consequences of PYCRs depletion could not be rescued by external supplementation with either proline or nucleotides. Overall, our data suggest that, despite the mechanisms underlying the role of proline metabolism in colorectal tumorigenesis remain elusive, targeting the proline biosynthesis pathway is a suitable approach for the development of novel anti-cancer therapies.


Assuntos
Neoplasias Colorretais
5.
Rapid Commun Mass Spectrom ; 36(6): e9245, 2022 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-34939243

RESUMO

RATIONALE: Acrylamide is classified as a probable human carcinogen that is metabolised to glycidamide, which can covalently bind to DNA. The aim of this study was to investigate the formation of N7-glycidamide guanine (N7-GA-Gua) adducts in human blood DNA following exposure to acrylamide present in carbohydrate-rich foods as part of the normal human diet. METHODS: Lymphocyte DNA was extracted from blood samples obtained from healthy human volunteers. Following thermal depurination of the DNA samples, N7-GA-Gua adducts were quantified using a validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) method incorporating a stable isotope labelled internal standard. Estimated dietary acrylamide intake was recorded by completion of food frequency questionnaires for the 24 hours prior to volunteer blood donation. RESULTS: An LC/MS/MS method was validated with a limit of detection of 0.25 fmol and a lower limit of quantitation of 0.50 fmol on column. N7-GA-Gua adducts were detected in human blood DNA with the levels ranging between 0.3 to 6.3 adducts per 108 nucleotides. The acrylamide intake was calculated from the food frequency questionnaires ranging between 20.0 and 78.6 µg. CONCLUSIONS: Identification and quantification of N7-GA-Gua adducts in the blood DNA of healthy volunteers suggests that dietary acrylamide exposure may lead to the formation of DNA adducts. This important finding warrants further investigation to ascertain a correlation between environmental/dietary acrylamide exposure and levels of DNA adducts.


Assuntos
Acrilamida/metabolismo , Cromatografia Líquida/métodos , Adutos de DNA/química , DNA/química , Exposição Dietética/efeitos adversos , Compostos de Epóxi/química , Guanina/química , Espectrometria de Massas em Tandem/métodos , Humanos , Linfócitos/química
6.
Am J Clin Nutr ; 113(5): 1115-1125, 2021 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-33675348

RESUMO

BACKGROUND: The dietary polyphenol resveratrol prevents various malignancies in preclinical models, including prostate cancer. Despite attempts to translate findings to humans, gaps remain in understanding pharmacokinetic-pharmacodynamic relations and how tissue concentrations affect efficacy. Such information is necessary for dose selection and is particularly important given the low bioavailability of resveratrol. OBJECTIVES: This study aimed to determine concentrations of resveratrol in prostate tissue of men after a dietary-achievable (5 mg) or pharmacological (1 g) dose. We then examined whether clinically relevant concentrations of resveratrol/its metabolites had direct anticancer activity in prostate cell lines. METHODS: A window trial was performed in which patients were allocated to 5 mg or 1 g resveratrol daily, or no intervention, before prostate biopsy. Patients (10/group) ingested resveratrol capsules for 7-14 d before biopsy, with the last dose [14C]-labeled, allowing detection of resveratrol species in prostate tissue using accelerator MS. Cellular uptake and antiproliferative properties of resveratrol/metabolites were assessed in cancer and nonmalignant cell cultures using HPLC with UV detection and cell counting, respectively. RESULTS: [14C]-Resveratrol species were detectable in prostate tissue of all patients analyzed, with mean ± SD concentrations of 0.08 ± 0.04 compared with 22.1 ± 8.2 pmol/mg tissue for the 5 mg and the 1 g dose, respectively. However, total [14C]-resveratrol equivalents in prostate were lower than we previously reported in plasma and colorectum after identical doses. Furthermore, resveratrol was undetectable in prostate tissue; instead, sulfate and glucuronide metabolites dominated. Although resveratrol reduced prostate cell numbers in vitro over 7 d, the concentrations required (≥10 µM) exceeded the plasma maximum concentration. Resveratrol mono-sulfates and glucuronides failed to consistently inhibit cell growth, partly due to poor cellular uptake. CONCLUSIONS: Low tissue concentrations of resveratrol species, coupled with weak antiproliferative activity of its conjugates, suggest daily doses of ≤1 g may not have direct effects on human prostate.This trial was registered at clinicaltrialsregister.eu as EudraCT 2007-002131-91.


Assuntos
Próstata/metabolismo , Resveratrol/metabolismo , Resveratrol/farmacocinética , Administração Oral , Antioxidantes/administração & dosagem , Antioxidantes/metabolismo , Antioxidantes/farmacocinética , Antioxidantes/uso terapêutico , Radioisótopos de Carbono , Linhagem Celular Tumoral , Dieta , Relação Dose-Resposta a Droga , Vias de Administração de Medicamentos , Humanos , Marcação por Isótopo , Masculino , Neoplasias da Próstata/prevenção & controle , Resveratrol/administração & dosagem , Resveratrol/uso terapêutico
7.
Cell Death Discov ; 6: 104, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33083024

RESUMO

The metabolism of the non-essential amino acid L-proline is emerging as a key pathway in the metabolic rewiring that sustains cancer cells proliferation, survival and metastatic spread. Pyrroline-5-carboxylate reductase (PYCR) and proline dehydrogenase (PRODH) enzymes, which catalyze the last step in proline biosynthesis and the first step of its catabolism, respectively, have been extensively associated with the progression of several malignancies, and have been exposed as potential targets for anticancer drug development. As investigations into the links between proline metabolism and cancer accumulate, the complexity, and sometimes contradictory nature of this interaction emerge. It is clear that the role of proline metabolism enzymes in cancer depends on tumor type, with different cancers and cancer-related phenotypes displaying different dependencies on these enzymes. Unexpectedly, the outcome of rewiring proline metabolism also differs between conditions of nutrient and oxygen limitation. Here, we provide a comprehensive review of proline metabolism in cancer; we collate the experimental evidence that links proline metabolism with the different aspects of cancer progression and critically discuss the potential mechanisms involved.

8.
Mol Nutr Food Res ; 62(16): e1800267, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29943914

RESUMO

SCOPE: Curcumin (from turmeric), has been extensively investigated for potential beneficial properties in numerous diseases. Most work has focused on supra-dietary concentrations/doses that would necessitate curcumin supplementation. However, much evidence instigating curcumin research is underpinned by epidemiological data based on low dietary intake via turmeric consumption. METHODS AND RESULTS: Here, a novel, highly sensitive liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS/MS) method for detection of curcuminoids is described. Assay sensitivity is demonstrated in a pilot pharmacokinetic volunteer study following ingestion of foodstuffs containing a standardized mass of turmeric, representative of daily consumption by certain South Asian populations. Free parent curcumin was detectable in plasma from one individual, reaching maximal plasma concentrations (Cmax ) of 3.2 nm. Curcumin conjugates were detected in all volunteers; Cmax for curcumin glucuronide is 47.6 ± 28.5 nm 30 min post-food, while Cmax for demethoxycurcumin glucuronide and curcumin sulfate is ≈2 nm. Curcumin and its major metabolites persist in plasma for at least 8 h. CONCLUSION: Despite poor absorption and rapid conjugation, dietary intake of standard culinary turmeric within complex food matrices furnished human plasma with detectable levels of curcuminoids. Whether sustained low systemic concentrations of these non-nutritive, biologically active, dietary components may have pharmacological activity for human health benefit, warrants further research.


Assuntos
Curcuma , Curcumina/análogos & derivados , Curcumina/análise , Glucuronídeos/sangue , Adulto , Calibragem , Cromatografia Líquida , Curcumina/metabolismo , Diarileptanoides , Feminino , Análise de Alimentos , Voluntários Saudáveis , Humanos , Limite de Detecção , Masculino , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem
9.
Biomed Chromatogr ; : e4280, 2018 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-29744910

RESUMO

Curcumin, derived from turmeric, has been extensively investigated for its broad spectrum of biological activities. Previously reported HPLC-UV methods have focussed on analysis of the parent compound. Here, a sensitive HPLC-UV method was developed and partially validated, then used for the simultaneous determination of curcumin and its glucuronide and sulfate metabolites in plasma and lung tissue from mice. The assay was applied to an in vivo pharmacokinetic study comparing formulated curcumin (Meriva™) with standard curcumin. Plasma levels of glucuronide and sulfate metabolites were 5- and 2-fold higher after Meriva™ administration compared with standard curcumin. In lung tissue, free curcumin was 4-fold higher following Meriva™ administration vs standard curcumin. This assay represents a rapid, cheap method for simultaneous detection of curcumin and its major metabolites that has applicability in pre-clinical settings.

10.
Sci Transl Med ; 7(298): 298ra117, 2015 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-26223300

RESUMO

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.


Assuntos
Adenoma/tratamento farmacológico , Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Estilbenos/administração & dosagem , Proteínas Quinases Ativadas por AMP/metabolismo , Adenoma/metabolismo , Adenoma/patologia , Animais , Autofagia/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Dieta Hiperlipídica , Relação Dose-Resposta a Droga , Humanos , Camundongos , Resveratrol , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
11.
Ann N Y Acad Sci ; 1348(1): 124-33, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26099829

RESUMO

To truly understand the mechanisms through which resveratrol exerts its biological effects, the key direct interactions between resveratrol and its target biomolecules must be identified. With an increasing number of biochemical tools to measure and quantify direct physical interactions between biomolecules, there have been around 20 proteins identified as having a specific affinity to resveratrol to date. Resveratrol has been described as a promiscuous molecule, and one would expect it to bind with numerous proteins, which would help explain why resveratrol appears to have so many health benefits and has been shown to act upon various different pathways related to a diverse range of conditions. The aim of this review is to present the direct protein targets of resveratrol that are currently known and highlight the consequences of direct binding and the methods used to identify the nature of these interactions.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Estilbenos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Resveratrol , Estilbenos/uso terapêutico
12.
Cancer Chemother Pharmacol ; 76(1): 179-85, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26017621

RESUMO

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.


Assuntos
Flavonóis/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Neoplasias da Próstata/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Autophagy ; 10(3): 524-5, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24419144

RESUMO

Resveratrol has many proposed health benefits, including the prevention of cancers, but its low bioavailability is considered a limiting factor in translating these effects to humans. Based on in vivo and clinical studies we have shown that resveratrol is indeed rapidly metabolized by phase II enzymes, and that resveratrol sulfates are deconjugated by steroid sulfatases to afford free resveratrol in vitro and in vivo and hence act as an intracellular reservoir for resveratrol. Further, we have demonstrated that at clinically achievable concentrations of resveratrol sulfate, parent resveratrol is regenerated within human colorectal cancer, but not normal epithelial cells, and is responsible for inducing autophagy with senescence selectively in cancer cells.


Assuntos
Anticarcinógenos/farmacologia , Autofagia/efeitos dos fármacos , Neoplasias Colorretais/patologia , Estilbenos/farmacologia , Sulfatos/farmacologia , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Humanos , Espaço Intracelular/efeitos dos fármacos , Resveratrol
14.
Sci Transl Med ; 5(205): 205ra133, 2013 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-24089405

RESUMO

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.


Assuntos
Autofagia , Senescência Celular , Espaço Intracelular/metabolismo , Estilbenos/metabolismo , Sulfatos/metabolismo , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células , Senescência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Neoplasias Colorretais/sangue , Glucuronídeos/sangue , Humanos , Espaço Intracelular/efeitos dos fármacos , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Resveratrol , Estilbenos/sangue , Estilbenos/farmacologia
15.
Cancer Prev Res (Phila) ; 6(2): 119-28, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23233733

RESUMO

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.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma/tratamento farmacológico , Colo/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Curcumina/farmacocinética , Aceitação pelo Paciente de Cuidados de Saúde , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Disponibilidade Biológica , Carcinoma/metabolismo , Carcinoma/patologia , Carcinoma/urina , Colo/efeitos dos fármacos , Colo/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/urina , Curcumina/administração & dosagem , Curcumina/efeitos adversos , Feminino , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Mucosa Intestinal/fisiopatologia , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Cooperação do Paciente/estatística & dados numéricos , Projetos Piloto , Fatores de Tempo
16.
Eur J Med Chem ; 54: 952-8, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22789812

RESUMO

A library of flavonol analogues was synthesised and evaluated as potential anticancer agents against a human prostate cancer cell line, 22rν1. Compounds 3, 8 and 11 (IC(50) 2.6, 3.3 and 4.0 µM respectively) showed potent cancer cell growth inhibition, comparable to the lead compound 3',4',5'-trimethoxyflavonol (1) (IC(50) 3.1 µM) and superior to the naturally occurring flavonols quercetin (16) and fisetin (22) (both >15 µM). Results indicate that the 3',4',5'- arrangement of either hydroxy (OH) or methoxy (OMe) residues is important for growth arrest of these cells and that the OMe analogues may be superior to their OH counterparts. Compounds 1, 3, 8 and 11 warrant further investigation as potential agents for the management of prostate cancer.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Flavonóis/síntese química , Flavonóis/farmacologia , Neoplasias da Próstata/patologia , Antineoplásicos/química , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Linhagem Celular Tumoral , Técnicas de Química Sintética , Estabilidade de Medicamentos , Flavonóis/química , Flavonóis/farmacocinética , Humanos , Interações Hidrofóbicas e Hidrofílicas , Masculino
17.
Biomed Chromatogr ; 26(12): 1559-66, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22454297

RESUMO

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.


Assuntos
Anticarcinógenos/metabolismo , Anticarcinógenos/farmacocinética , Flavonóis/metabolismo , Flavonóis/farmacocinética , Animais , Anticarcinógenos/análise , Anticarcinógenos/química , Cromatografia Líquida de Alta Pressão/métodos , Feminino , Flavonoides/análise , Flavonoides/química , Flavonoides/metabolismo , Flavonoides/farmacocinética , Flavonóis/análise , Flavonóis/química , Mucosa Intestinal/química , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Masculino , Redes e Vias Metabólicas , Camundongos , Camundongos Endogâmicos C57BL , Sensibilidade e Especificidade , Distribuição Tecidual
18.
Cancer Chemother Pharmacol ; 67(2): 255-63, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20364427

RESUMO

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.


Assuntos
Citosol/metabolismo , Flavonoides/metabolismo , Flavonoides/farmacocinética , Microssomos Hepáticos/metabolismo , Adulto , Animais , Área Sob a Curva , Sulfonatos de Arila/metabolismo , Biocatálise , Sangue/metabolismo , Feminino , Flavonas/metabolismo , Flavonoides/administração & dosagem , Flavonoides/sangue , Glucuronatos/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Cinética , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Adulto Jovem
19.
Cancer Res ; 70(19): 7392-9, 2010 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-20841478

RESUMO

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.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Estilbenos/uso terapêutico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacocinética , Processos de Crescimento Celular/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Terapia Combinada , Feminino , Humanos , Imuno-Histoquímica , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-Idade , Resveratrol , Estilbenos/efeitos adversos , Estilbenos/farmacocinética
20.
Cancer Prev Res (Phila) ; 3(8): 929-39, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20628003

RESUMO

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.


Assuntos
Carcinoma/prevenção & controle , Neoplasias Colorretais/prevenção & controle , Resistencia a Medicamentos Antineoplásicos/genética , Flavonoides/uso terapêutico , Genes p53/fisiologia , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Carcinoma/genética , Quimioprevenção , Neoplasias Colorretais/genética , Avaliação Pré-Clínica de Medicamentos , Células HCT116 , Humanos , Camundongos , Camundongos Nus , Camundongos Transgênicos , Quercetina/análogos & derivados , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
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