RESUMEN
PURPOSE: Omega-3 fatty acids have been shown to reduce the incidence and slow the growth of mammary gland cancer in rodent models. Since exposure to dietary components during the critical developmental times of gestation and lactation may alter risk for mammary gland cancer in females, we tested whether exposure to increased levels of long-chain omega-3 fatty acids from fish oils would be preventive or promotional to mammary gland cancer in the offspring. METHODS: Normal SV129 female mice were fed AIN 76 diets containing either 10% corn oil (control, 50% omega 6, n-6) or 5% of an omega-3 (n-3) fatty acid concentrate (fish oil 60% n-3) + 5% canola oil (10% n-3 + 20% n-6). Females were then mated with C(3)1 TAg transgenic mice. At weaning (3 weeks), pups were randomized to either the corn (C) or fish oil (F) diet, 15-17 mice per group. Four experimental groups were generated: FF, FC, CF and CC. Tumor incidence and multiplicity were assessed at the following time points 120, 130 and 140 days of age. A panel of genes encoding signal transduction proteins were analyzed in mammary glands at 130 days. RESULTS: Mice never exposed to fish oil (CC group) had a significantly higher incidence and multiplicity of mammary gland tumors than mice exposed to fish oil throughout life (FF group). Mice exposed to fish oil during a portion of life (CF or FC) had intermediate tumor incidences and multiplicities. Results also indicate that maternal consumption of fish oil increased the expression of genes associated with immune system activation (Ccl20, Cd5, Il2, Lef1, Lta). CONCLUSIONS: Adequate omega-3 fatty acids in the maternal diet may reduce the risk for mammary gland cancer in the offspring. If humans make dietary change by consuming more omega-3 fat instead of corn oil with 0% omega 3 fat, breast cancer may be reduced in the next generation.
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Ácidos Grasos Omega-3 , Aceites de Pescado , Animales , Carcinogénesis , Aceite de Maíz , Femenino , Ratones , Ratones TransgénicosRESUMEN
The consumption of omega-3 polyunsaturated fatty acids (n-3 PUFA) is associated with a reduced risk of breast cancer. Studies in animals and in vitro have demonstrated mechanisms that could explain this apparent effect, but clinical and epidemiological studies have returned conflicting results on the practical benefits of dietary n-3 PUFA for prevention of breast cancer. Effects are often only significant within a population when comparing the highest n-3 PUFA consumption group to the lowest n-3 group or highest n-6 group. The beneficial effects of n-3 PUFA eicosapentaenoic and docosahexaenoic on the risk of breast cancer are dose dependent and are negatively affected by total n-6 consumption. The majority of the world population, including the most highly developed regions, consumes insufficient n-3 PUFA to significantly reduce breast cancer risk. This review discusses the physiological and dietary context in which reduction of breast cancer risk may occur, some proposed mechanisms of action and meaningful recommendations for consumption of n-3 PUFA in the diet of developed regions.
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Neoplasias de la Mama/prevención & control , Grasas de la Dieta/administración & dosificación , Ácidos Grasos Omega-3/administración & dosificación , Animales , Neoplasias de la Mama/metabolismo , Grasas de la Dieta/metabolismo , Ácidos Docosahexaenoicos/metabolismo , Ácido Eicosapentaenoico/metabolismo , Ácidos Grasos Omega-3/metabolismo , Femenino , HumanosRESUMEN
Colorectal cancer, unlike many other malignancies, may be preventable. Recent studies have demonstrated an inverse association between nut consumption and incidence of colon cancer; however, the underlying mechanisms are not fully understood. An emerging concept suggests that microribonucleic acids (miRNAs) may help explain the relationship between walnut consumption and decreased colorectal neoplasia risk. Seven days after HT-29 colon cancer cell injection, mice were randomized to either control or walnut diets for 25 days of diet treatment. Thirty samples of tumor and of omental adipose were analyzed to determine changes in lipid composition in each dietary group. In the tumors of the walnut-containing diet, we found significant increases in α-linolenic, eicosapentaenoic, docosahexaenoic and total omega-3 acids, and a decrease in arachidonic acid, as compared to the control diet. Final tumor size measured at sacrifice was negatively associated with percentage of total omega-3 fatty acid composition (r=-0.641, P=.001). MicroRNA expression analysis of colorectal tumor tissue revealed decreased expression of miRNAs 1903, 467c and 3068 (P<.05) and increased expression of miRNA 297a* (P=.0059) in the walnut-treated group as compared to control diet. Our results indicate that changes in the miRNA expression profiles likely affect target gene transcripts involved in pathways of anti-inflammation, antivascularization, antiproliferation and apoptosis. We also demonstrate the incorporation of protective fatty acids into colonic epithelium of walnut-fed mice, which may independently alter miRNA expression profiles itself. Future studies of the mechanism of widespread miRNA regulation by walnut consumption are needed to offer potential prognostic and therapeutic targets.
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Neoplasias Colorrectales/prevención & control , Ácidos Grasos Omega-3/metabolismo , Alimentos Funcionales , Regulación Neoplásica de la Expresión Génica , Juglans , MicroARNs/metabolismo , Nueces , Animales , Carcinoma/metabolismo , Carcinoma/patología , Carcinoma/prevención & control , Colon/metabolismo , Colon/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Femenino , Alimentos Funcionales/análisis , Perfilación de la Expresión Génica , Células HT29 , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Grasa Intraabdominal/metabolismo , Grasa Intraabdominal/patología , Juglans/química , Ratones Desnudos , Nueces/química , Distribución Aleatoria , Carga Tumoral , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Capsaicin, the pungent ingredient of chili peppers, displays potent anti-neoplastic activity in a wide array of human cancer cells. The present manuscript examines the signaling pathways underlying the apoptotic activity of capsaicin in human small cell lung cancer (SCLC) in vitro and in vivo. Studies in neuronal cells show that capsaicin exerts its biological activity via the transient receptor potential vanilloid (TRPV) superfamily of cation-channel receptors. The TRPV family is comprised of six members (TRPV1-6). Capsaicin is a known agonist of the TRPV1 receptor. We observed that capsaicin-induced apoptosis in human SCLC cells was mediated via the TRPV receptor family; however it was independent of TRPV1. Surprisingly, the apoptotic activity of capsaicin required the TRPV6 receptor. Depletion of TRPV6 receptor by siRNA methodology abolished the apoptotic activity of capsaicin in SCLC cells. Immunostaining and ELISA showed that TRPV6 receptor was robustly expressed on human SCLC tissues (from patients) and SCLC cell lines but almost absent in normal lung tissues. This correlates with our results that capsaicin induced very little apoptosis in normal lung epithelial cells. The pro-apoptotic activity of capsaicin was mediated by the intracellular calcium and calpain pathway. The treatment of human SCLC cells with capsaicin increased the activity of calpain 1 and 2 by threefold relative to untreated SCLC cells. Such calpain activation, in response to capsaicin, was downstream of the TRPV6 receptor. Taken together, our data provide insights into the mechanism underlying the apoptotic activity of capsaicin in human SCLCs.
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Anticarcinógenos/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Canales de Calcio/metabolismo , Calpaína/metabolismo , Capsaicina/farmacología , Neoplasias Pulmonares/patología , Carcinoma Pulmonar de Células Pequeñas/patología , Canales Catiónicos TRPV/metabolismo , Animales , Calcio/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Xenoinjertos , Humanos , Masculino , Ratones Desnudos , Trasplante de Neoplasias , Transducción de SeñalRESUMEN
Colorectal cancer is the third leading cause of cancer-related death in the western world. In vitro and in vivo experiments showed that omega-3 polyunsaturated fatty acids (n-3 PUFAs) can attenuate the proliferation of cancer cells, including colon cancer, and increase the efficacy of various anticancer drugs. However, these studies address the effects of n-3 PUFAs on the bulk of the tumor cells and not on the undifferentiated colon cancer stem-like cells (CSLCs) that are responsible for tumor formation and maintenance. CSLCs have also been linked to the acquisition of chemotherapy resistance and to tumor relapse. Colon CSLCs have been immunophenotyped using several antibodies against cellular markers including CD133, CD44, EpCAM, and ALDH. Anti-CD133 has been used to isolate a population of colon cancer cells that retains stem cells properties (CSLCs) from both established cell lines and primary cell cultures. We demonstrated that the n-3 PUFA, eicosapentaenoic acid (EPA), was actively incorporated into the membrane lipids of COLO 320 DM cells. 25 uM EPA decreased the cell number of the overall population of cancer cells, but not of the CD133 (+) CSLCs. Also, we observed that EPA induced down-regulation of CD133 expression and up-regulation of colonic epithelium differentiation markers, Cytokeratin 20 (CK20) and Mucin 2 (MUC2). Finally, we demonstrated that EPA increased the sensitivity of COLO 320 DM cells (total population) to both standard-of-care chemotherapies (5-Fluorouracil and oxaliplatin), whereas EPA increased the sensitivity of the CD133 (+) CSLCs to only 5-Fluorouracil.
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Antígenos CD/metabolismo , Antineoplásicos/farmacología , Ácido Eicosapentaenoico/farmacología , Glicoproteínas/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Péptidos/metabolismo , Antígeno AC133 , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Fluorouracilo/farmacología , Humanos , Compuestos Organoplatinos/farmacología , OxaliplatinoRESUMEN
Targeting the nuclear factor kappa B (NFκB) pathway is proposed as therapy for chronic lymphocytic leukemia (CLL). We hypothesized that an omega-3 fatty acids (n-3) supplement would suppress NFκB activation in lymphocytes of Rai Stage 0-1 CLL patients. The initial dose of 2.4 g n-3/day was gradually increased to 7.2 g n-3/day. After n-3 consumption: 1) plasma n-3 increased; 2) NFκB activation was suppressed in lymphocytes; 3) in vitro sensitivity of lymphocytes to doxorubicin was increased; and 4) expression of 32 genes in lymphocytes was significantly decreased.
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Ácidos Grasos Omega-3/administración & dosificación , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/metabolismo , Linfocitos/metabolismo , FN-kappa B/antagonistas & inhibidores , Anciano , Anciano de 80 o más Años , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Suplementos Dietéticos , Doxorrubicina/uso terapéutico , Ácidos Grasos Omega-3/efectos adversos , Ácidos Grasos Omega-3/sangre , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Leucemia Linfocítica Crónica de Células B/sangre , Leucemia Linfocítica Crónica de Células B/genética , Linfocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , FN-kappa B/genética , FN-kappa B/metabolismo , ARN Mensajero/genéticaRESUMEN
Recent case-controlled clinical studies show that bronchioalveolar carcinomas (BAC) are correlated with smoking. Nicotine, the addictive component of cigarettes, accelerates cell proliferation through nicotinic acetylcholine receptors (nAChR). In this study, we show that human BACs produce acetylcholine (ACh) and contain several cholinergic factors including acetylcholinesterase (AChE), choline acetyltransferase (ChAT), choline transporter 1 (CHT1, SLC5A7), vesicular acetylcholine transporter (VAChT, SLC18A3), and nACh receptors (AChRs, CHRNAs). Nicotine increased the production of ACh in human BACs, and ACh acts as a growth factor for these cells. Nicotine-induced ACh production was mediated by α7-, α3ß2-, and ß3-nAChRs, ChAT and VAChT pathways. We observed that nicotine upregulated ChAT and VAChT. Therefore, we conjectured that VAChT antagonists, such as vesamicol, may suppress the growth of human BACs. Vesamicol induced potent apoptosis of human BACs in cell culture and nude mice models. Vesamicol did not have any effect on EGF or insulin-like growth factor-II-induced growth of human BACs. siRNA-mediated attenuation of VAChT reversed the apoptotic activity of vesamicol. We also observed that vesamicol inhibited Akt phosphorylation during cell death and that overexpression of constitutively active Akt reversed the apoptotic activity of vesamicol. Taken together, our results suggested that disruption of nicotine-induced cholinergic signaling by agents such as vesamicol may have applications in BAC therapy.
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Acetilcolina/metabolismo , Adenocarcinoma Bronquioloalveolar/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Piperidinas/farmacología , Transducción de Señal/efectos de los fármacos , Adenocarcinoma Bronquioloalveolar/metabolismo , Adenocarcinoma Bronquioloalveolar/patología , Animales , Western Blotting , Línea Celular Tumoral , Células Cultivadas , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Desnudos , Fármacos Neuromusculares Despolarizantes/farmacología , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Interferencia de ARN , Proteínas de Transporte Vesicular de Acetilcolina/antagonistas & inhibidores , Proteínas de Transporte Vesicular de Acetilcolina/genética , Proteínas de Transporte Vesicular de Acetilcolina/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Small cell lung cancer (SCLC) demonstrates a strong etiological association with smoking. Although cigarette smoke is a mixture of about 4,000 compounds, nicotine is the addictive component of cigarette smoke. Several convergent studies have shown that nicotine promotes angiogenesis in lung cancers via the α7-nicotinic acetylcholine receptor (α7-nAChR) on endothelial cells. Therefore, we conjectured that α7-nAChR antagonists may attenuate nicotine-induced angiogenesis and be useful for the treatment of human SCLC. For the first time, our study explores the anti-angiogenic activity of MG624, a small-molecule α7-nAChR antagonist, in several experimental models of angiogenesis. We observed that MG624 potently suppressed the proliferation of primary human microvascular endothelial cells of the lung (HMEC-Ls). Furthermore, MG624 displayed robust anti-angiogenic activity in the Matrigel, rat aortic ring and rat retinal explant assays. The anti-angiogenic activity of MG624 was assessed by two in vivo models, namely the chicken chorioallantoic membrane model and the nude mice model. In both of these experimental models, MG624 inhibited angiogenesis of human SCLC tumors. Most importantly, the administration of MG624 was not associated with any toxic side effects, lethargy or discomfort in the mice. The anti-angiogenic activity of MG624 was mediated via the suppression of nicotine-induced FGF2 levels in HMEC-Ls. MG624 decreased nicotine-induced early growth response gene 1 (Egr-1) levels in HMEC-Ls, and reduced the levels of Egr-1 on the FGF2 promoter. Consequently, this process decreased FGF2 levels and angiogenesis. Our findings suggest that the anti-angiogenic effects of MG624 could be useful in anti-angiogenic therapy of human SCLCs.
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Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Neovascularización Fisiológica/efectos de los fármacos , Antagonistas Nicotínicos/farmacología , Compuestos de Amonio Cuaternario/farmacología , Receptores Nicotínicos/metabolismo , Transducción de Señal/efectos de los fármacos , Estilbenos/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Pollos , Regulación hacia Abajo/efectos de los fármacos , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Humanos , Pulmón/irrigación sanguínea , Pulmón/citología , Ratones , Ratones Desnudos , Microvasos/citología , Microvasos/efectos de los fármacos , Modelos Biológicos , Nicotina/farmacología , Antagonistas Nicotínicos/química , Compuestos de Amonio Cuaternario/química , Ratas , Estilbenos/química , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
Prostate cancer incidence and mortality are high in the Western world and high ω-6/ω-3 PUFA in the Western diet may be a contributing factor. We investigated whether changing from a diet that approximates ω-6 fat content of the Western diet to a high ω-3 fat diet at adulthood might reduce prostate cancer risk. Female SV 129 mice that had consumed a high ω-6 diet containing corn oil for 2 weeks were bred with homozygous C3(1)Tag transgenic male mice. All male offspring were weaned to the corn oil diet (CO) until postpuberty when half of the male offspring were transferred to a high ω-3 diet containing canola oil and fish oil concentrate (FS). High ω-3 diet increased ω-3 and decreased ω-6 fat content of mice tissues. Average weights of prostate and genitourinary bloc were significantly lower in mice consuming high ω-3 diet at adulthood (CO-FS) than mice fed a lifetime high ω-6 diet (CO-CO). There was slower progression of tumorigenesis in dorsalateral prostate of CO-FS than in CO-CO mice. CO-FS mice had slightly lower plasma testosterone level at 24 and 40 weeks, significantly lower estradiol level at 40 weeks and significantly less expressed androgen receptor (AR) in the dorsalateral prostate at 40 weeks than CO-CO mice. Consumption of high ω-3 diet lowered the expression of genes expected to increase proliferation and decrease apoptosis in dorsalateral prostate. Our results suggest that consumption of high ω-3 diet slows down prostate tumorigenesis by lowering estradiol, testosterone and AR levels, promoting apoptosis and suppressing cell proliferation in C3(1)Tag mice.
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Ácidos Grasos Omega-3/administración & dosificación , Neoplasias de la Próstata/prevención & control , Animales , Antígenos Virales de Tumores/genética , Apoptosis , Proliferación Celular , Estrógenos/sangre , Ácidos Grasos Omega-6/administración & dosificación , Femenino , Lípidos/análisis , Masculino , Ratones , FN-kappa B/antagonistas & inhibidores , FN-kappa B/fisiología , Tamaño de los Órganos , Próstata/patología , Receptores Androgénicos/análisis , Testosterona/sangre , Aumento de PesoRESUMEN
Walnuts contain multiple ingredients that, individually, have been shown to slow cancer growth, including omega-3 fatty acids, antioxidants, and phytosterols. In previous research, consumption of walnuts has slowed the growth of implanted breast cancers. We wanted to determine whether regular walnut consumption might reduce the risk for developing cancer. Homozygous male C(3)1 TAg mice were bred with female SV129 mice consuming either the control AIN-76 diet or the walnut-containing diet. At weaning, the female hemizygous pups were randomized to control or walnut-containing diets and followed for tumor development. Compared to a diet without walnuts, consumption of walnuts significantly reduced tumor incidence (fraction of mice with at least one tumor), multiplicity (number of glands with tumor/mouse), and size. Gene expression analyses indicated that consumption of the walnut diet altered expression of multiple genes associated with proliferation and differentiation of mammary epithelial cells. A comparison with another dietary intervention indicated that the omega 3 content alone did not account for the extent of tumor suppression due to the walnut. The results of this study indicate that walnut consumption could contribute to a healthy diet to reduce risk for breast cancer.
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Transformación Celular Neoplásica/efectos de los fármacos , Dieta , Grasas de la Dieta/administración & dosificación , Juglans , Neoplasias Mamarias Animales/tratamiento farmacológico , Nueces , Animales , Western Blotting , Peso Corporal , Cromatografía de Gases , Femenino , Masculino , Ratones , Ratones Transgénicos , Factores de Riesgo , Aumento de PesoRESUMEN
BACKGROUND: Results from increasing numbers of in vitro and in vivo studies have demonstrated that omega 3 fatty acids incorporated in cell culture media or in the diet of the animals can suppress the growth of cancers. When human clinical trials are initiated to determine the ability of omega 3 fatty acids to alter growth or response to chemotherapeutic interventions of cancers, it will be essential to determine the omega 3 intake of individuals in the trial to determine compliance with consumption of the supplement and to correlate with endpoints of efficacy. We wondered if the fatty acid composition of RBCs might accurately indicate incorporation of omega 3 fatty acids in the WBCs. In this report we determine and compare the changes in fatty acid compositions of red blood cells and white blood cells in response to consumption of three doses of an omega 3 fatty acid supplement. RESULTS: We found that the fraction of omega 3 fatty acids in both red blood cells and white blood cells increased following consumption of the supplement. There was a linear, dose responsive increase in the fraction of omega 3 fatty acids in red blood cells but the increase in omega 3 in white blood cells was not linear. The magnitude of increase in omega 3 fatty acids was different between the two cell types. CONCLUSIONS: Fatty acid analysis of red blood cells is a good measure of compliance with supplement consumption. However, fatty acid analysis of white blood cells is needed to correlate changes in fatty acid composition of white blood cells with other biochemical changes in the white blood cells. TRIAL REGISTRATION: ClinicalTrials.gov NCT00899353.