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/químicaRESUMEN
Pancreatic cancer is a disease with a significantly poor prognosis. Despite modern advances in other medical, surgical, and oncologic therapy, the outcome from pancreatic cancer has improved little over the last 40 years. To improve the management of this difficult disease, trials investigating the use of dietary and parenteral fish oils rich in omega-3 (ω-3) fatty acids, exhibiting proven anti-inflammatory and anticarcinogenic properties, have revealed favorable results in pancreatic cancers. Proteomics is the large-scale study of proteins that attempts to characterize the complete set of proteins encoded by the genome of an organism and that, with the use of sensitive mass spectrometric-based techniques, has allowed high-throughput analysis of the proteome to aid identification of putative biomarkers pertinent to given disease states. These biomarkers provide useful insight into potentially discovering new markers for early detection or elucidating the efficacy of treatment on pancreatic cancers. Here, our review identifies potential proteomic-based biomarkers in pancreatic cancer relating to apoptosis, cell proliferation, angiogenesis, and metabolic regulation in clinical studies. We also reviewed proteomic biomarkers from the administration of ω-3 fatty acids that act on similar anticarcinogenic pathways as above and reflect that proteomic studies on the effect of ω-3 fatty acids in pancreatic cancer will yield favorable results.
Asunto(s)
Biomarcadores/sangre , Ácidos Grasos Omega-3/administración & dosificación , Aceites de Pescado/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , Proteómica/métodos , Ensayos Clínicos como Asunto , Suplementos Dietéticos , Humanos , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Neoplasias Pancreáticas/sangreRESUMEN
Many cancers contain cell subpopulations that display characteristics of stem cells. These cells are characterised by their ability to self-renew, form differentiated progeny and develop resistance to chemotherapeutic strategies. Cancer stem cells may utilise many of the same signalling pathways as normal stem cells including Wnt, Notch and Hedgehog. The dietary agent curcumin exerts a plethora of anti-carcinogenic effects both in vitro and in vivo, and can also inhibit many of the signalling pathways associated with stem cell biology. Emerging evidence suggests that curcumin can exert its anti-carcinogenic activity via targeting cancer stem cells through the disruption of stem cell signalling pathways. In this review we summarise the ability of curcumin to interfere with signalling pathways Wnt, Hedgehog, Notch, Signal Transducers and Activator (STAT) and interleukin-8, and report curcumin-induced changes in function and properties of cancer stem cells. We present evidence that the effects of curcumin on cancer stem cells mediate, or contribute to, its anti-carcinogenic activity.
Asunto(s)
Anticarcinógenos/farmacología , Curcumina/farmacología , Células Madre Neoplásicas/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Interleucina-8/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo , Factores de Transcripción STAT/genética , Factores de Transcripción STAT/metabolismo , Transducción de Señal , Proteínas Wnt/genética , Proteínas Wnt/metabolismoRESUMEN
BACKGROUND AND PURPOSE: Elevating levels of endocannabinoids with inhibitors of fatty acid amide hydrolase (FAAH) is a major focus of pain research, purported to be a safer approach devoid of cannabinoid receptor-mediated side effects. Here, we have determined the effects of sustained pharmacological inhibition of FAAH on inflammatory pain behaviour and if pharmacological inhibition of FAAH was as effective as genetic deletion of FAAH on pain behaviour. EXPERIMENTAL APPROACH: Effects of pre-treatment with a single dose, versus 4 day repeated dosing with the selective FAAH inhibitor, URB597 (i.p. 0.3 mg·kg⻹), on carrageenan-induced inflammatory pain behaviour and spinal pro-inflammatory gene induction were determined in rats. Effects of pain induction and of the drug treatments on levels of arachidonoyl ethanolamide (AEA), palmitoyl ethanolamide (PEA) and oleolyl ethanolamide (OEA) in the spinal cord were determined. KEY RESULTS: Single, but not repeated, URB597 treatment significantly attenuated the development of inflammatory hyperalgesia (P < 0.001, vs. vehicle-treated animals). Neither mode of URB597 treatment altered levels of AEA, PEA and OEA in the hind paw, or carrageenan-induced paw oedema. Single URB597 treatment produced larger increases in AEA, PEA and OEA in the spinal cord, compared with those after repeated administration. Single and repeated URB597 treatment decreased levels of immunoreactive N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) in the spinal cord and attenuated carrageenan-induced spinal pro-inflammatory gene induction. CONCLUSION AND IMPLICATIONS: Changes in the endocannabinoid system may contribute to the loss of analgesic effects following repeated administration of low dose URB597 in this model of inflammatory pain.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Benzamidas/farmacología , Carbamatos/farmacología , Endocannabinoides/metabolismo , Dolor/tratamiento farmacológico , Amidas , Animales , Ácidos Araquidónicos/metabolismo , Conducta Animal/efectos de los fármacos , Benzamidas/administración & dosificación , Carbamatos/administración & dosificación , Modelos Animales de Enfermedad , Esquema de Medicación , Etanolaminas/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/fisiopatología , Masculino , Ácidos Oléicos/metabolismo , Dolor/etiología , Ácidos Palmíticos/metabolismo , Alcamidas Poliinsaturadas/metabolismo , Ratas , Ratas Sprague-Dawley , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismoRESUMEN
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 TisularRESUMEN
OBJECTIVE: To investigate the impact of an experimental model of osteoarthritis (OA) on spinal nociceptive processing and the role of the inhibitory endocannabinoid system in regulating sensory processing at the spinal level. METHODS: Experimental OA was induced in rats by intraarticular injection of sodium mono-iodoacetate (MIA), and the development of pain behavior was assessed. Extracellular single-unit recordings of wide dynamic range (WDR) neurons in the dorsal horn were obtained in MIA-treated rats and saline-treated rats. The levels of endocannabinoids and the protein and messenger RNA levels of the main synthetic enzymes for the endocannabinoids (N-acyl phosphatidylethanolamine phospholipase D [NAPE-PLD] and diacylglycerol lipase α [DAGLα]) in the spinal cord were measured. RESULTS: Low-weight (10 gm) mechanically evoked responses of WDR neurons were significantly (P < 0.05) facilitated 28 days after MIA injection compared with the responses in saline-treated rats, and spinal cord levels of anandamide and 2-arachidonoyl glycerol (2-AG) were increased in MIA-treated rats. Protein levels of NAPE-PLD and DAGLα, which synthesize anandamide and 2-AG, respectively, were elevated in the spinal cords of MIA-treated rats. The functional role of endocannabinoids in the spinal cords of MIA-treated rats was increased via activation of cannabinoid 1 (CB(1) ) and CB(2) receptors, and blockade of the catabolism of anandamide had significantly greater inhibitory effects in MIA-treated rats compared with control rats. CONCLUSION: Our findings provide new evidence for altered spinal nociceptive processing indicative of central sensitization and for adaptive changes in the spinal cord endocannabinoid system in an experimental model of OA. The novel control of spinal cord neuronal responses by spinal cord CB(2) receptors suggests that this receptor system may be an important target for the modulation of pain in OA.