RESUMO
SCOPE: A dose-ranging study is performed using young estrogen-depleted rats to determine whether dietary isoliquiritigenin (ILQ) alters bone metabolism and if the effects are associated with estrogen receptor signaling. METHODS AND RESULTS: Six-week-old rats (ovariectomized at 4 weeks of age) are fed diets containing 0, 100, 250, or 750 ppm ILQ (n = 5/treatment) for 7 days. Gene expression in femur and uterus, blood markers of bone turnover, body composition, and uterine weight and epithelial cell height are determined. Because ILQ lowers bone resorption, the effect of ILQ on in vitro differentiation of osteoclasts from bone marrow of mice is assessed. Treatment resulted in a dose-dependent increases in serum ILQ but no changes in serum osteocalcin, a marker of global bone formation. Contrastingly, ILQ administration results in reduced serum CTX-1, a marker of global bone resorption, and reduces tartrate resistant acid phosphatase expression in osteoclast culture. ILQ treatment and endogenous estrogen production had limited overlap on gene expression in femur and uterus. However, uterine epithelial cell hyperplasia is observed in two of five animals treated with 750 ppm. CONCLUSIONS: In conclusion, dietary ILQ reduces bone resorption in vivo and osteoclast differentiation in vitro, by mechanisms likely differing from actions of ovarian hormones.
Assuntos
Reabsorção Óssea , Osteoclastos , Animais , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo , Diferenciação Celular , Chalconas , Estrogênios/metabolismo , Feminino , Humanos , Camundongos , Ovariectomia , Ratos , Fosfatase Ácida Resistente a Tartarato/metabolismo , Fosfatase Ácida Resistente a Tartarato/farmacologiaRESUMO
Equol (EQ) is a prominent microbial metabolite of the soy isoflavone, daidzein, with estrogen-like properties. The major soy isoflavone, genistein (GEN), stimulated growth of estrogen-dependent breast cancer (EDBC) cells in vitro and tumor growth in vivo but EQ did not. To understand possible interactions of EQ and GEN on EDBC, EQ was used with GEN in combination in vitro and in vivo. Effects of EQ, GEN and EQ + GEN were evaluated using MCF-7 and T47D EDBC. Ovariectomized athymic mice were used as a model for in vivo tumor growth. Dietary EQ had no effect on MCF-7 tumor growth and the absence of effect was confirmed using a T47D EDBC in vivo model. EQ alone or in combination with GEN increased EDBC cell proliferation in vitro. EQ alone neither stimulated EDBC tumor growth in vivo at various doses nor suppressed tumor growth induced by dietary GEN. In summary, EQ has similar estrogenic effect as GEN in vitro but does not interact with GEN on EDBC tumor growth. Based on the evidence presented here, dietary EQ is unlikely to have estrogenic effects in vivo.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Equol/uso terapêutico , Genisteína/uso terapêutico , Fitoestrógenos/uso terapêutico , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Suplementos Nutricionais , Feminino , Humanos , Glândulas Mamárias Animais/patologia , Camundongos Endogâmicos BALB C , Camundongos NusRESUMO
Deep-frying is a popular form of food preparation used globally and throughout in the United States. Each time dietary oils are heated to deep-frying temperatures, they undergo chemical alterations that result in a new matrix of lipid structures. These lipid products include triglyceride dimers, polymers, oxidized triglycerides, and cyclic monomers, which raises nutritional concerns about associations between these lipid products and heightened health risks. Reports of associations between thermally abused frying oil and deleterious health outcomes currently exist, yet there is little information concerning the effects of thermally abused frying oil consumption and the progression of breast cancer. This study used a late-stage breast cancer murine model and in vivo bioluminescent imaging to monitor progression of metastasis of 4T1 tumor cells in animals consuming fresh soybean oil (SBO) and a thermally abused frying oil (TAFO). Bioluminescent and histologic examinations demonstrated that TAFO consumption resulted in a marked increase of metastatic lung tumor formation compared to SBO consumption. Further, in animals consuming the TAFO treatment diet, metastatic tumors in the lung displayed a 1.4-fold increase in the Ki-67 marker of cellular proliferation and RNA-sequencing analysis of the hepatic tissue revealed a dietary-induced modulation of gene expression in the liver.
Assuntos
Proliferação de Células , Culinária/métodos , Gorduras Insaturadas na Dieta/toxicidade , Modelos Animais de Doenças , Temperatura Alta/efeitos adversos , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Animais/patologia , Animais , Apoptose , Feminino , Neoplasias Pulmonares/etiologia , Neoplasias Mamárias Animais/etiologia , Camundongos , Camundongos Endogâmicos BALB C , Células Tumorais CultivadasRESUMO
Approximately 30% of metastatic breast cancers harbor estrogen receptor α (ERα) mutations associated with resistance to endocrine therapy and reduced survival. Consistent with their constitutive proliferation, T47D and MCF7 cells in which wild-type ERα is replaced by the most common mutations, ERαY537S and ERαD538G, exhibit partially estrogen-independent gene expression. A novel invasion/dissociation/rebinding assay demonstrated that the mutant cells have a higher tendency to dissociate from invasion sites and rebind to a second site. Compared to ERαD538G breast tumors, ERαY537S tumors exhibited a dramatic increase in lung metastasis. Transcriptome analysis showed that the ERαY537S and ERαD538G mutations each elicit a unique gene expression profile. Gene set enrichment analysis showed Myc target pathways are highly induced in mutant cells. Moreover, chromatin immunoprecipitation showed constitutive, fulvestrant-resistant, recruitment of ERα mutants to the Myc enhancer region, resulting in estrogen-independent Myc overexpression in mutant cells and tumors. Knockdown and virus transduction showed Myc is necessary and sufficient for ligand-independent proliferation of the mutant cells but had no effect on metastasis-related phenotypes. Thus, Myc plays a key role in aggressive proliferation-related phenotypes exhibited by breast cancer cells expressing ERα mutations.
Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Antagonistas do Receptor de Estrogênio/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Fulvestranto/farmacologia , Mutação , Proteínas Proto-Oncogênicas c-myc/metabolismo , Sítios de Ligação , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Movimento Celular , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos/genética , Elementos Facilitadores Genéticos , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Células MCF-7 , Invasividade Neoplásica , Proteínas Proto-Oncogênicas c-myc/genética , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Despite existent fortification initiatives in the Philippines, approximately 50% of the population still suffers from iron deficiency anemia (IDA), mainly in rural areas. Fortification of staple foods has been proved successful in China and Vietnam. Coconut spiced vinegar (SV) is an inexpensive, widely available, and culturally acceptable condiment in Filipino households; however, no technical evidence exists on its potential as fortification vehicle. This study aimed to physicochemically characterize and evaluate the consumer acceptability of SV fortified with ferrous sulfate (FS), ferrous fumarate (FF), or sodium iron ethylenediaminetetraacetate (NaFeEDTA) at 0.2 mg Fe/mL. Iron fortificants were added directly to SV, vortexed, and stored for analysis. A nonfortified SV served as a control. Physicochemical analyses (pH, titratable acidity, color, turbidity, and iron recovery) were conducted from 0 to 6 months postfortification. Consumer acceptability (9-point hedonic scale: color, appearance, aroma, sourness, and overall acceptability) was conducted using 1-month fortified vinegar in 96 students and 27 women. Iron recovery of fortified samples was high and similar (>97%) after 3 days of fortification and remained >87% at 6 months postfortification. All samples had minimum acidity of 5.31% and pH between 3.12 and 3.3. Color difference against the control followed the next order: SV-NaFeEDTA < SV-FS = SV-FF. Among students, acceptability of SV-FS and SV-FF were lower than the control and SV-NaFeEDTA for all attributes (P < 0.05) except aroma. In women, overall acceptability and aroma were not different among samples (P > 0.05). Overall, SV-NaFeEDTA had similar acceptability to the control, and was the most accepted fortified vinegar. SV-NaFeEDTA shows potential (in terms of physicochemical stability and consumer acceptability) to be used as an iron-delivery vehicle to address IDA. PRACTICAL APPLICATION: The present study addresses the technical and organoleptic challenges of fortifying Filipino spiced vinegar with three iron sources. About 50% of the Filipino population (especially women and children) still suffers from iron deficiency, thus, more effective ways to deliver iron are needed. If successful, our study could pose as the base milestone for implementing mass iron fortification of spiced vinegar, given its frequent consumption and reach of all socioeconomic pockets of the Filipino population. Our aim is to improve the overall nutritional health of at-risk populations, and our study is one step closer to achieve this goal.
Assuntos
Ácido Acético/química , Alimentos Fortificados/análise , Ferro/química , Especiarias/análise , Adolescente , Adulto , Anemia Ferropriva/prevenção & controle , Cor , Ácido Edético , Feminino , Compostos Férricos , Compostos Ferrosos/análise , Humanos , Masculino , Pessoa de Meia-Idade , Odorantes , Filipinas , Sensação , Paladar , Adulto JovemRESUMO
This study investigated the efficacy of components of licorice root to alter performance on two different recognition tasks, a hippocampus-sensitive metric change in object location (MCOL) task and a striatum-sensitive double object recognition (DOR) task. Isoliquiritigenin (ISL), licorice root extract (LRE), and whole licorice root powder (LRP) were assessed. Young adult female rats were ovariectomized (OVX) and exposed to ISL, LRE or LRP at 0.075%, 0.5% or 5% respectively in the diet. An estradiol group was included as a positive control based on our prior findings. Rats were allowed to explore two objects for three 5-min study trials (separated by 3-min intervals) before a fourth 5-min test trial where the objects were moved closer together (MCOL task) or replaced with two new objects (DOR task). Rats typically habituate to the objects across the three study trials. An increase in object exploration time in the test trial suggests the rat detected the change. Estradiol improved MCOL performance and impaired DOR performance, similar to previously shown effects of estradiol and other estrogens, which tend to improve learning and memory on hippocampus-sensitive tasks and impair striatum-sensitive cognition. LRP had no effect on recognition while exposure to ISL and LRE improved MCOL performance. Exposure to ISL, LRE and LRP failed to attenuate DOR, contrary to effects of estradiol shown here and to previous reports in young-adult OVX rats. These findings suggest components of licorice root may prove to be effective therapies targeting memory enhancement without unintended deleterious cognitive effects.
Assuntos
Estrogênios/farmacologia , Glycyrrhiza/química , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Reconhecimento Psicológico/efeitos dos fármacos , Percepção Visual/efeitos dos fármacos , Animais , Estradiol/farmacologia , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Memória/efeitos dos fármacos , Ovariectomia , Ratos , Ratos Long-Evans , Navegação Espacial/efeitos dos fármacosRESUMO
Although polymeric nanoconjugates (NCs) hold great promise for the treatment of cancer patients, their clinical utility has been hindered by the lack of efficient delivery of therapeutics to targeted tumor sites. Here, we describe an albumin-functionalized polymeric NC (Alb-NC) capable of crossing the endothelium barrier through a caveolae-mediated transcytosis pathway to better target cancer. The Alb-NC is prepared by nanoprecipitation of doxorubicin (Doxo) conjugates of poly(phenyl O-carboxyanhydrides) bearing aromatic albumin-binding domains followed by subsequent surface decoration of albumin. The administration of Alb-NCs into mice bearing MCF-7 human breast cancer xenografts with limited tumor vascular permeability resulted in markedly increased tumor accumulation and anti-tumor efficacy compared to their conventional counterpart PEGylated NCs (PEG-NCs). The Alb-NC provides a simple, low-cost and broadly applicable strategy to improve the cancer targeting efficiency and therapeutic effectiveness of polymeric nanomedicine.
Assuntos
Albuminas/química , Permeabilidade Capilar , Doxorrubicina/química , Endotélio Vascular/metabolismo , Neoplasias Mamárias Experimentais/tratamento farmacológico , Nanoconjugados/química , Albuminas/efeitos adversos , Albuminas/farmacocinética , Animais , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , TranscitoseRESUMO
BACKGROUND: Metastasis refers to the spread of a primary tumor cell from the primary site to other locations in the body and it is generally associated with the severity of a tumor. Extract of Ginkgo biloba (EGb) contains various bioactive compounds and it exerts beneficial effects including improvements in brain function and reduced risk of cardiovascular diseases. On the other hand, increased risk of thyroid and liver cancers by EGb have been reported in animals. METHODS: A colon cancer metastasis model was established using intrasplenic injection of a human colon cancer cell line, SW620-luc in athymic mice to investigate the potential impact of EGb on colon cancer progression. After tumor establishment, EGb was intraperitonically injected daily for 5 wks. RESULTS: EGb significantly increased the rate of metastasis in mouse liver and decreased the number of necrotic and apoptotic cells in the metastatic liver when compared to the control. Meanwhile, EGb significantly induced proliferation of tumor cells in the metastatic liver, indicated by increased staining of Ki67 and H3S10p. mRNA expression of genes involved in cell cycle, metastasis, apoptosis, and oxidative stress were altered by EGb treatment in livers with tumors. Moreover, EGb activated the stress-responsive MAPK pathways in the liver with metastatic tumors. CONCLUSIONS: EGb exacerbated liver metastasis in a mouse colon cancer metastasis model. This is potentially due to the increased tumor cell proliferation involving stimulated MAPK pathways.
Assuntos
Neoplasias do Colo , Ginkgo biloba , Neoplasias Hepáticas , Fígado/efeitos dos fármacos , Extratos Vegetais , Animais , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Camundongos , Camundongos Nus , Metástase Neoplásica , Extratos Vegetais/efeitos adversos , Extratos Vegetais/química , Extratos Vegetais/farmacologiaRESUMO
Genistein is a phytoestrogen found in soy and soy-based products. Previously, we found that genistein adversely affected estradiol levels and follicle growth in vitro. Proper hormone production and follicle growth are key regulators of normal fertility. Therefore, we hypothesized that genistein adversely affects female fertility and pregnancy outcomes. To test this hypothesis, we dosed sexually mature female CD-1 mice (35days) with 0, 300, 500, or 1000ppm genistein for 30, 60, 150, and 240days. At the end of the dosing periods, we measured mating rate, pregnancy rate, fertility rate, gestation time, parturition time, pup mortality, litter size, average pup weight, and estradiol and progesterone levels. We found that chronic, preconception exposure to genistein affects gestation time, parturition time, litter size, pup weight, and pup mortality. Additionally, genistein exposure for 240days appears to have a protective effect on fertility rate, but does not affect hormone levels in vivo.
Assuntos
Genisteína/toxicidade , Fitoestrógenos/toxicidade , Reprodução/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Dieta , Estradiol/sangue , Feminino , Fertilidade/efeitos dos fármacos , Tamanho da Ninhada de Vivíparos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/crescimento & desenvolvimento , Masculino , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Ovário/efeitos dos fármacos , Ovário/crescimento & desenvolvimento , Gravidez , Progesterona/sangue , Útero/efeitos dos fármacos , Útero/crescimento & desenvolvimentoRESUMO
Breast cancer metastasizes to bone in the majority of patients with advanced disease. We investigated the effects of inadequate dietary calcium (Ca) on bone turnover, tumor growth, and bone response to tumor in tibia inoculated with 4T1 mammary carcinoma cells. Nine-month-old female Balb/c mice were placed on an adequate Ca (5 g/kg diet, n = 30) or low Ca (80 mg/kg diet, n = 31) diet for 14 days, then injected intratibially with 1,000 4T1 cells (transfected with luciferase for bioluminescence imaging), and sacrificed at 5, 10, or 21 days post-inoculation (n = 7-10 mice/group). Control mice (n = 6/group) were injected with carrier and sacrificed at 10 days post-inoculation. Tibiae with muscle intact were excised and evaluated by microcomputed tomography and histology. In vivo bioluminescent imaging revealed that 4T1 cells metastasized to lung. Therefore, lungs were removed for quantification of tumor. Mice fed low Ca exhibited higher bone turnover and higher tibial lesion scores than mice fed adequate Ca. Lesion severity, manifested as cortical osteolysis and periosteal woven bone formation, and tumor cell infiltration to muscle, increased with time, irrespective of diet. However, for most skeletal endpoints the rates of increase were greater in mice consuming low Ca compared to mice consuming adequate Ca. Infiltration of tumor cells into adjacent muscle, but not metastasis to lung, was also greater in mice consuming low Ca diet. The findings suggest that high bone turnover due to Ca insufficiency results in greater local mammary tumor cell growth, cortical osteolysis, woven bone formation, and invasion to muscle in mice.
Assuntos
Cálcio da Dieta/farmacologia , Neoplasias Mamárias Animais/patologia , Tíbia/patologia , Carga Tumoral/efeitos dos fármacos , Animais , Remodelação Óssea/efeitos dos fármacos , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/efeitos dos fármacos , Osso Esponjoso/patologia , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Camundongos Endogâmicos BALB C , Metástase Neoplásica , Tíbia/diagnóstico por imagem , Tíbia/efeitos dos fármacos , Microtomografia por Raio-XRESUMO
The negative impact of chemotherapy on cognitive function in cancer patients has gained increasing attention in the last decade. Whilst the short-term acute effects on cognition are expected following chemotherapy, the persistence of such impairments in the long-term is still in question. This is despite clinical evidence indicating cognitive difficulties may persist well beyond treatment and affect quality of life. In the present study, we assessed the long-term (3 months) cognitive impact of chemotherapy in a mouse model intended to mimic the human female post-menopausal population receiving chemotherapy for breast cancer. Ovariectomized, female, C57BL/6J mice received two doses of Doxorubicin, Cyclophosphamide, and 5-Fluorouracil or saline vehicle (control), separated by one week. During this interval, mice received BrdU injections to label dividing cells. Results indicate a persistent impairment in learning and recall (1h, 24h and 48h) on the Morris water maze, reduced survival and differentiation of new neurons (BrdU+/NeuN+), and a persistent decline in proliferation of new cells (Ki67(+)) in the dentate gyrus. Locomotor activity, motor performance, and anxiety-like behavior were unaffected. We further evaluated the efficacy of a diet enriched in omega-3-fatty acids (DHA+EPA+DPA), in reversing long-term chemotherapy deficits but no rescue was observed. The model described produces long-term cognitive and cellular impairments from chemotherapy that mimic those observed in humans. It could be useful for identifying mechanisms of action and to test further the ability of lifestyle interventions (e.g., diet) for ameliorating chemotherapy-induced cognitive impairments.
Assuntos
Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Transtornos da Memória/induzido quimicamente , Neurogênese/efeitos dos fármacos , Aprendizagem Espacial/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Contagem de Células , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ciclofosfamida/efeitos adversos , Doxorrubicina/efeitos adversos , Comportamento Exploratório/efeitos dos fármacos , Ácidos Graxos Ômega-3/administração & dosagem , Feminino , Fluoruracila/efeitos adversos , Antígeno Ki-67/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Ovariectomia , Fosfopiruvato Hidratase/metabolismoRESUMO
Malignant osteolysis associated with inoperable primary bone tumors and multifocal skeletal metastases remains a challenging clinical problem in cancer patients. Nanomedicine that is able to target and deliver therapeutic agents to diseased bone sites could potentially provide an effective treatment option for different types of skeletal cancers. Here, we report the development of polylactide nanoparticles (NPs) loaded with doxorubicin (Doxo) and coated with bone-seeking pamidronate (Pam) for the targeted treatment of malignant skeletal tumors. In vivo biodistribution of radiolabeled targeted Pam-NPs demonstrated enhanced bone tumor accumulation and prolonged retention compared with nontargeted NPs. In a murine model of focal malignant osteolysis, Pam-functionalized, Doxo-loaded NPs (Pam-Doxo-NPs) significantly attenuated localized osteosarcoma (OS) progression compared with nontargeted Doxo-NPs. Importantly, we report on the first evaluation to our knowlege of Pam-Doxo-NPs in dogs with OS, which possess tumors of anatomic size and physiology comparable to those in humans. The repeat dosing of Pam-Doxo-NPs in dogs with naturally occurring OS indicated the therapeutic was well tolerated without hematologic, nonhematologic, and cardiac toxicities. By nuclear scintigraphy, the biodistribution of Pam-Doxo-NPs demonstrated malignant bone-targeting capability and exerted measurable anticancer activities as confirmed with percent tumor necrosis histopathology assessment.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Ósseas/tratamento farmacológico , Difosfonatos/administração & dosagem , Doxorrubicina/administração & dosagem , Nanoconjugados/administração & dosagem , Osteólise/tratamento farmacológico , Animais , Difosfonatos/farmacocinética , Doxorrubicina/toxicidade , Feminino , Camundongos , Camundongos Endogâmicos BALB C , PamidronatoRESUMO
Breast cancer (BC) is the leading cancer in women worldwide. Metastasis occurs in stage IV BC with bone and lung being common metastatic sites. Here we evaluate the effects of the aromatase inhibitor letrozole on BC micro-metastatic tumor growth in bone and lung metastasis in intact and ovariectomized (OVX) mice with murine estrogen receptor negative (ER-) BC cells inoculated in tibia. Forty-eight BALB/c mice were randomly assigned to one of four groups: OVX, OVX + Letrozole, Intact, and Intact + Letrozole, and injected with 4T1 cells intra-tibially. Letrozole was subcutaneously injected daily for 23 days at a dose of 1.75 µg/g body weight. Tumor progression was monitored by bioluminescence imaging (BLI). Following necropsy, inoculated tibiae were scanned via µCT and bone response to tumor was scored from 0 (no ectopic mineralization/osteolysis) to 5 (extensive ectopic mineralization/osteolysis). OVX mice had higher tibial pathology scores indicative of more extensive bone destruction than intact mice, irrespective of letrozole treatment. Letrozole decreased serum estradiol levels and reduced lung surface tumor numbers in intact animals. Furthermore, mice receiving letrozole had significantly fewer tumor colonies and fewer proliferative cells in the lung than OVX and intact controls based on H&E and Ki-67 staining, respectively. In conclusion, BC-inoculated OVX animals had higher tibia pathology scores than BC-inoculated intact animals and letrozole reduced BC metastases to lungs. These findings suggest that, by lowering systemic estrogen level and/or by interacting with the host organ, the aromatase inhibitor letrozole has the potential to reduce ER- BC metastasis to lung.
Assuntos
Neoplasias Ósseas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Micrometástase de Neoplasia/tratamento farmacológico , Nitrilas/administração & dosagem , Triazóis/administração & dosagem , Animais , Inibidores da Aromatase/administração & dosagem , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Letrozol , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Camundongos , Micrometástase de Neoplasia/patologiaRESUMO
To identify new pathways of estrogen action and novel estrogen receptor α (ERα) biomodulators, we performed high throughput screening and used follow on assays and bioinformatics to identify small molecule ERα inhibitors with a novel mode of action. These studies led to identification of rapid extranuclear activation of the endoplasmic reticulum stress sensor, the unfolded protein response (UPR), as a new pathway of estrogen-ERα action. Moreover, increasing evidence indicates that the mechanism underlying anticipatory activation of the UPR is shared among steroid and peptide hormones and is conserved from insects to humans. It is likely that this newly unveiled extranuclear pathway is used by diverse mitogenic hormones to prepare cells for the increased protein folding load that will occur during subsequent cell proliferation. Demonstrating biological relevance, elevated expression of a UPR gene signature in ERα positive breast cancer is a powerful new prognostic marker tightly correlated with subsequent resistance to tamoxifen, tumor recurrence and poor survival. In addition, overexpression of epidermal growth factor receptor and HER2/neu is positively correlated with increased UPR activation in breast cancer. This review describes recent research that demonstrates the importance of anticipatory UPR activation in therapy resistant tumors and discusses a promising small molecule biomodulator that inhibits tumor growth by tuning this UPR signaling pathway.
Assuntos
Neoplasias da Mama/metabolismo , Resposta a Proteínas não Dobradas/fisiologia , Animais , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/fisiologia , Receptores ErbB/genética , Receptores ErbB/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Resposta a Proteínas não Dobradas/genéticaRESUMO
Genistein is a naturally occurring isoflavone phytoestrogen commonly found in plant products such as soybeans, lentils, and chickpeas. Genistein, like other phytoestrogens, has the potential to mimic, enhance, or impair the estradiol biosynthesis pathway, thereby potentially altering ovarian follicle growth. Previous studies have inconsistently indicated that genistein exposure may alter granulosa cell proliferation and hormone production, but no studies have examined the effects of genistein on intact antral follicles. Thus, this study was designed to test the hypothesis that genistein exposure inhibits follicle growth and steroidogenesis in intact antral follicles. To test this hypothesis, antral follicles isolated from CD-1 mice were cultured with vehicle (dimethyl sulfoxide; DMSO) or genistein (6.0 and 36µM) for 18-96h. Every 24h, follicle diameters were measured to assess growth. At the end of each culture period, the media were pooled to measure hormone levels, and the cultured follicles were collected to measure expression of cell cycle regulators and steroidogenic enzymes. The results indicate that genistein (36µM) inhibits growth of mouse antral follicles. Additionally, genistein (6.0 and 36µM) increases progesterone, testosterone, and dehydroepiandrosterone (DHEA) levels, but decreases estrone and estradiol levels. The results also indicate that genistein alters the expression of steroidogenic enzymes at 24, 72 and 96h, and the expression of cell cycle regulators at 18h. These data indicate that genistein exposure inhibits antral follicle growth by inhibiting the cell cycle, alters sex steroid hormone levels, and dysregulates steroidogenic enzymes in cultured mouse antral follicles.
Assuntos
Genisteína/toxicidade , Folículo Ovariano/efeitos dos fármacos , Fitoestrógenos/toxicidade , 17-Hidroxiesteroide Desidrogenases/genética , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas de Ciclo Celular/genética , Sistema Enzimático do Citocromo P-450/genética , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Feminino , Hormônios Esteroides Gonadais/metabolismo , Camundongos , Folículo Ovariano/crescimento & desenvolvimento , Folículo Ovariano/metabolismo , Fosfoproteínas/genéticaRESUMO
Licorice root extracts are often consumed as botanical dietary supplements by menopausal women as a natural alternative to pharmaceutical hormone replacement therapy. In addition to their components liquiritigenin (Liq) and isoliquiritigenin (Iso-Liq), known to have estrogenic activity, licorice root extracts also contain a number of other flavonoids, isoflavonoids, and chalcones. We have investigated the estrogenic activity of 7 of these components, obtained from an extract of Glycyrrhiza glabra powder, namely Glabridin (L1), Calycosin (L2), Methoxychalcone (L3), Vestitol (L4), Glyasperin C (L5), Glycycoumarin (L6), and Glicoricone (L7), and compared them with Liq, Iso-Liq, and estradiol (E2). All components, including Liq and Iso-Liq, have low binding affinity for estrogen receptors (ERs). Their potency and efficacy in stimulating the expression of estrogen-regulated genes reveal that Liq and Iso-Liq and L2, L3, L4, and L6 are estrogen agonists. Interestingly, L3 and L4 have an efficacy nearly equivalent to E2 but with a potency ca. 10,000-fold less. The other components, L1, L5 and L7, acted as partial estrogen antagonists. All agonist activities were reversed by the antiestrogen, ICI 182,780, or by knockdown of ERα with siRNA, indicating that they are ER dependent. In HepG2 hepatoma cells stably expressing ERα, only Liq, Iso-Liq, and L3 stimulated estrogen-regulated gene expression, and in all cases gene stimulation did not occur in HepG2 cells lacking ERα. Collectively, these findings classify the components of licorice root extracts as low potency, mixed ER agonists and antagonists, having a character akin to that of selective estrogen receptor modulators or SERMs.
Assuntos
Suplementos Nutricionais , Antagonistas de Estrogênios/farmacologia , Estrogênios/farmacologia , Glycyrrhiza/química , Raízes de Plantas/química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Feminino , Flavanonas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Antígeno Ki-67/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Células MCF-7 , Espectroscopia de Ressonância Magnética , Extratos Vegetais/farmacologia , Receptores de Estrogênio/metabolismoRESUMO
SCOPE: We studied the impact of dietary supplementation with licorice root components on diet-induced obesity, fat accumulation, and hepatic steatosis in ovariectomized C57BL/6 mice as a menopause model. MATERIALS AND METHODS: We evaluated the molecular and physiological effects of dietary licorice root administered to ovariectomized C57BL/6 mice as root powder (LRP), extracts (LRE), or isolated isoliquiritigenin (ILQ) on reproductive (uterus and mammary gland) and nonreproductive tissues important in regulating metabolism (liver, perigonadal, perirenal, mesenteric, and subcutaneous fat). Quantitative outcome measures including body weight, fat distribution (magnetic resonance imaging), food consumption, bone density and weight (Dual-energy X-ray absorptiometry), and gene expression were assessed by the degree of restoration to the preovariectomized health state. We characterized histological (H&E and oil red O staining) and molecular properties (expression of certain disease markers) of these tissues, and correlated these with metabolic phenotype as well as blood levels of bioactives. CONCLUSION: Although LRE and ILQ provided some benefit, LRP was the most effective in reducing body weight gain, overall fat deposition, liver steatosis, and expression of hepatic lipid synthesis genes following ovariectomy. Our data demonstrate that licorice root provided improvement of multiple metabolic parameters under conditions of low estrogen and high-fat diets without stimulating reproductive tissues.
Assuntos
Suplementos Nutricionais , Glycyrrhiza/química , Metabolismo dos Lipídeos/efeitos dos fármacos , Glândulas Mamárias Animais/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/dietoterapia , Absorciometria de Fóton , Animais , Distribuição da Gordura Corporal , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Feminino , Flavanonas/farmacologia , Camundongos Endogâmicos C57BL , Ovariectomia , Raízes de Plantas/química , Útero/efeitos dos fármacos , Aumento de Peso/efeitos dos fármacosRESUMO
Previously, we observed that wild yam (Dioscorea villosa) root extract (WYRE) was able to activate GATA3 in human breast cancer cells targeting epigenome. This study aimed to find out if dioscin (DS), a bioactive compound of WYRE, can modulate GATA3 functions and cellular invasion in human breast cancer cells. MCF-7 and MDA-MB-231 cells were treated in the absence/presence of various concentrations of DS and subjected to gene analysis by RT-qPCR, immunoblotting, and immunocytochemistry. We determined the ability of MDA-MB-231 cells to migrate into wound area and examined the effects of DS on cellular invasion using invasion assay. DS reduced cell viability of both cell lines in a concentration and time-dependent manner. GATA3 expression was enhanced by DS (5.76 µM) in MDA-MB-231 cells. DS (5.76 µM)-treated MDA-MB-231 cells exhibited the morphological characteristic of epithelial-like cells; mRNA expression of DNMT3A, TET2, TET3, ZFPM2 and E-cad were increased while TET1, VIM and MMP9 were decreased. Cellular invasion of MDA-MB-231 was reduced by 65 ± 5% in the presence of 5.76 µM DS. Our data suggested that DS-mediated pathway could promote GATA3 expression at transcription and translation levels. We propose that DS has potential to be used as an anti-invasive agent in breast cancer.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Dioscorea/química , Diosgenina/análogos & derivados , Extratos Vegetais/administração & dosagem , Raízes de Plantas/química , Antineoplásicos/administração & dosagem , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Diosgenina/administração & dosagem , Relação Dose-Resposta a Droga , Humanos , Células MCF-7 , Invasividade Neoplásica , Fitosteróis/administração & dosagem , Saponinas/administração & dosagem , Resultado do TratamentoRESUMO
We report the design and development of redox-responsive chain-shattering polymeric therapeutics (CSPTs). CSPTs were synthesized by condensation polymerization and further modified with poly(ethylene glycol) (PEG) via "Click" reaction. Size-controlled CSPT nanoparticles (NPs) were formed through nanoprecipitation with high drug loading (up to 18%); the particle size increased in a concentration dependent manner. Drug release from particles was well controlled over 48 h upon redox triggering. The anticancer efficacy of the CSPT NPs was validated both in vitro and in vivo.
Assuntos
Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/toxicidade , Células MCF-7/efeitos dos fármacos , Nanopartículas/química , Paclitaxel/uso terapêutico , Polietilenoglicóis/química , Polímeros/síntese química , Animais , Química Farmacêutica , Doxorrubicina/química , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Células MCF-7/química , Camundongos , Oxirredução , Paclitaxel/química , Tamanho da Partícula , Polimerização , Polímeros/químicaRESUMO
Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes.