RESUMEN
INTRODUCTION: The third-generation of aromatase inhibitors (AIs)-Exemestane (Exe), Letrozole (Let), and Anastrozole (Ana)-is the main therapeutic approach applied for estrogen receptor-positive (ER+) breast cancer (BC), the most common neoplasm in women worldwide. Despite their success, the development of resistance limits their efficacy. Genistein (G), a phytoestrogen present in soybean, has promising anticancer properties in ER+ BC cells, even when combined with anticancer drugs. Thus, the potential beneficial effects of combining G with AIs were investigated in sensitive (MCF7-aro) and resistant (LTEDaro) BC cells. METHODS: The effects on cell proliferation and expression of aromatase, ERα/ERß, and AR receptors were evaluated. RESULTS: Unlike the combination of G with Ana or Let, which negatively affects the Ais' therapeutic efficacy, G enhanced the anticancer properties of the steroidal AI Exe, increasing the antiproliferative effect and apoptosis relative to Exe. The hormone targets studied were not affected by this combination when compared with Exe. CONCLUSIONS: This is the first in vitro study that highlights the potential benefit of G as an adjuvant therapy with Exe, emphasizing, however, that soy derivatives widely used in the diet or applied as auxiliary medicines may increase the risk of adverse interactions with nonsteroidal AIs used in therapy.
Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Femenino , Humanos , Inhibidores de la Aromatasa/farmacología , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Genisteína/farmacología , Genisteína/uso terapéutico , Letrozol , Antineoplásicos/uso terapéutico , Nitrilos/uso terapéuticoRESUMEN
Pain caused by the tumor or aromatase inhibitors (AIs) is a disabling symptom in breast cancer survivors. Their mechanisms are unclear, but pro-algesic and inflammatory mediators seem to be involved. Kinins are endogenous algogenic mediators associated with various painful conditions via B1 and B2 receptor activation, including chemotherapy-induced pain and breast cancer proliferation. We investigate the involvement of the kinin B1 and B2 receptors in metastatic breast tumor (4T1 breast cancer cells)-caused pain and in aromatase inhibitors (anastrozole or letrozole) therapy-associated pain. A protocol associating the tumor and antineoplastic therapy was also performed. Kinin receptors' role was investigated via pharmacological antagonism, receptors protein expression, and kinin levels. Mechanical and cold allodynia and muscle strength were evaluated. AIs and breast tumor increased kinin receptors expression, and tumor also increased kinin levels. AIs caused mechanical allodynia and reduced the muscle strength of mice. Kinin B1 (DALBk) and B2 (Icatibant) receptor antagonists attenuated these effects and reduced breast tumor-induced mechanical and cold allodynia. AIs or paclitaxel enhanced breast tumor-induced mechanical hypersensitivity, while DALBk and Icatibant prevented this increase. Antagonists did not interfere with paclitaxel's cytotoxic action in vitro. Thus, kinin B1 or B2 receptors can be a potential target for treating the pain caused by metastatic breast tumor and their antineoplastic therapy.
Asunto(s)
Antineoplásicos , Dolor en Cáncer , Neoplasias , Ratones , Animales , Inhibidores de la Aromatasa/farmacología , Inhibidores de la Aromatasa/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Receptor de Bradiquinina B2/metabolismo , Receptor de Bradiquinina B1/metabolismo , Bradiquinina/farmacología , Dolor , PaclitaxelRESUMEN
The benign prostatic hyperplasia (BPH) is the main source of lower urinary tract symptoms. The BPH is a common age-dependent disease and tamsulosin is an α1-adrenoceptor blocker widely prescribed for BPH. Beyond the common adverse effects of tamsulosin, increased diagnosis of dementia after prescription was observed. Importantly, a clinical study suggested that tamsulosin may exert antidepressant effects in BPH patients. Considering the expression of α1-adrenoceptors in the brain, this study aimed to investigate the effects of tamsulosin in the forced swimming and open field tests in mice. For this, tamsulosin (0.001-1 mg/kg) was orally administered subacutely (1, 5 and 23 hr) and acutely (60 min) before tests. Mifepristone (10 mg/kg), a glucocorticoid receptor antagonist, and aminoglutethimide (10 mg/kg), a streoidogenesis inhibitor, were intraperitoneally injected before tamsulosin to investigate the role of the hypothalamic-pituitary-adrenal axis in the mediation of tamsulosin-induced effects. Subacute and acute administrations of tamsulosin increased the immobility time in the first exposition to an inescapable stressful situation. In the re-exposition to the swim task, controls displayed a natural increase in the immobility time, and the treatment with tamsulosin further increased this behavioral parameter. Tamsuslosin did not affect spontaneous locomotion neither in naïve nor in stressed mice. Our findings also showed that mifepristone and aminoglutethimide prevented the tamsulosin-induced increase in the immobility time in the first and second swimming sessions, respectively. In conclusion, tamsulosin may contribute to increased susceptibility to depressive-like behaviors, by facilitating the acquisition of a passive stress-copying strategy. These effects seem to be dependent on endogenous glucocorticoids.
Asunto(s)
Adaptación Psicológica/efectos de los fármacos , Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Inhibidores de la Aromatasa/farmacología , Depresión/inducido químicamente , Antagonistas de Hormonas/farmacología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Receptores de Glucocorticoides/antagonistas & inhibidores , Tamsulosina/farmacología , Antagonistas de Receptores Adrenérgicos alfa 1/administración & dosificación , Aminoglutetimida/farmacología , Animales , Inhibidores de la Aromatasa/administración & dosificación , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Antagonistas de Hormonas/administración & dosificación , Ratones , Mifepristona/farmacología , Tamsulosina/administración & dosificaciónRESUMEN
PURPOSE: Flap endonuclease 1 (FEN1) is up-regulated by estrogen (17ß-estradiol, E2) and related to cisplatin resistance of human breast cancer cells. Letrozole, an aromatase inhibitor, suppresses the change of testosterone into estrogen and is frequently used to treat breast cancer. However, the effects of letrozole on FEN1 expression and cisplatin sensitivity in breast cancer cells overexpressing aromatase have not been revealed. METHODS: The expression of FEN1 and the proteins in ERK/Elk-1 signaling were evaluated by RT-PCR and Western blot. Cisplatin sensitivity was explored through CCK-8 and flow cytometry analysis, respectively. FEN1 siRNAs and FEN1 expression plasmid were transfected into cells to down-regulate or up-regulate FEN1 expression. The promotor activity of FEN1 was detected using luciferase reporter assay. RESULTS: FEN1 down-regulation improved cisplatin sensitivity of breast cancer cells overexpressing aromatase. Letrozole down-regulated FEN1 expression and increased cisplatin sensitivity. The sensitizing effect of letrozole to cisplatin was dependent on FEN1 down-regulation. FEN1 overexpression could block the sensitizing effect of letrozole to cisplatin. Testosterone up-regulated the promotor activity, protein expression of FEN1, and phosphorylation of ERK/Elk-1, which could be eliminated by both letrozole and MEK1/2 inhibitor U0126. Letrozole down-regulated FEN1 expression in an ERK/Elk-1-dependent manner. CONCLUSIONS: Our findings clearly demonstrate that letrozole improves cisplatin sensitivity of breast cancer cells overexpressing aromatase via down-regulation of FEN1 and suggest that a combined use of letrozole and cisplatin may be a potential treatment protocol for relieving cisplatin resistance in human breast cancer.
Asunto(s)
Aromatasa/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Cisplatino/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Endonucleasas de ADN Solapado/antagonistas & inhibidores , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Letrozol/farmacología , Antineoplásicos/farmacología , Aromatasa/química , Inhibidores de la Aromatasa/farmacología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular , Regulación hacia Abajo , Femenino , Endonucleasas de ADN Solapado/genética , Endonucleasas de ADN Solapado/metabolismo , Humanos , Transducción de Señal , Células Tumorales CultivadasRESUMEN
Aromatase inhibitors (AIs) have been used to recover height loss due to their capacity to delay growth plate closure. Long-term studies describing final heights are needed to determine the efficacy and safety profiles of these drugs for the treatment of impaired growth. This study aims to identify the therapeutic efficiency of AIs in improve growth and to describe potential adverse effects during treatment. Retrospective data analysis of 96 adolescents, among which 22 patients already attained near-final height, were followed at outpatient clinics of two referral centers. Patients were all in puberty and present idiopathic decrease in predicted adult height. Patients were treated with Anastrozole (ANZ: 1 mg/day) or Letrozole (LTZ: 2.5 mg/day) with/without recombinant human growth hormone (0.05 mg/kg/day) for 1.0 to 3.5 years (2.1±1.2 years). Height gain, body mass index, lipid, liver enzyme, gonadotropins and testosterone levels were described before and at the end of treatment. Predicted adult height (PAH) and NF height were compared with the TH. The height SDS (adjusted to bone age) significantly increased (p<0.05) in all groups [0.8±0.7 (ANZ), 0.7±0.7 (ANZ+GH), 0.3±0.5 (LTZ), and 1.2±0.8 (LTZ+GH)]; the latter group exhibited the highest increment of PAH and growth recovery to the TH (p<0.004). No significant side effects were observed. AI treatment, especially when used in association with GH was able to improve growth and the attainment of familial target height.
Asunto(s)
Inhibidores de la Aromatasa/farmacología , Estatura/efectos de los fármacos , Hormona del Crecimiento/farmacología , Adolescente , Determinación de la Edad por el Esqueleto , Factores de Edad , Antropometría , Niño , Humanos , MasculinoRESUMEN
PURPOSE: To evaluate the effects of letrozole (Ltz) in carcinogen+estrogen-induced endometrial hyperplasia. METHODS: BALB/c female mice were divided into four groups of 12 animals each receiving an intrauterine dose of N-ethyl-N-nitrosourea (ENU) and weekly subcutaneous injections of estradiol hexaidrobenzoate (EHB), except for group I(control). The groups were divided in I (control), II (ENU+EHB), III (ENU+EHB+MPA) and IV (ENU+EHB+Ltz). Group III also received intramuscular injections of MPA (medroxy progesterone acetate) every four weeks, while group IV received oral doses of Ltz daily. At the end of 16 weeks, the animals were sacrificed, and blood samples were collected for the measurement of serum estradiol and progesterone levels. Uterine histological sections were made to evaluate the presence of endometrial proliferative lesions. Differences between groups were evaluated with student's t test, ANOVA and chi-square test. RESULTS: Groups ENU+EHB, ENU+EHB+MPA and ENU+EHB+Ltz showed varying degrees of endometrial hyperplasia. The incidence of hyperplasia in groups ENU+EHB and ENU+EHB+Ltz was higher and more severe than in group ENU+EHB+MPA. Control group showed lower levels of serum estradiol than the other groups. CONCLUSION: There was no evidence that letrozole could act as an antiestrogenic drug in the development of endometrial proliferative lesions.
Asunto(s)
Inhibidores de la Aromatasa/farmacología , Carcinogénesis/efectos de los fármacos , Hiperplasia Endometrial/tratamiento farmacológico , Nitrilos/farmacología , Triazoles/farmacología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/etiología , Animales , Antineoplásicos Hormonales/farmacología , Inhibidores de la Aromatasa/uso terapéutico , Carcinogénesis/patología , Hiperplasia Endometrial/inducido químicamente , Hiperplasia Endometrial/patología , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/etiología , Endometrio/efectos de los fármacos , Endometrio/patología , Estradiol/sangre , Etilnitrosourea , Femenino , Letrozol , Acetato de Medroxiprogesterona/farmacología , Ratones Endogámicos BALB C , Nitrilos/uso terapéutico , Progesterona/sangre , Reproducibilidad de los Resultados , Factores de Tiempo , Resultado del Tratamiento , Triazoles/uso terapéuticoRESUMEN
PURPOSE: To evaluate the effects of letrozole (Ltz) in carcinogen+estrogen-induced endometrial hyperplasia. METHODS: BALB/c female mice were divided into four groups of 12 animals each receiving an intrauterine dose of N-ethyl-N-nitrosourea (ENU) and weekly subcutaneous injections of estradiol hexaidrobenzoate (EHB), except for group I(control). The groups were divided in I (control), II (ENU+EHB), III (ENU+EHB+MPA) and IV (ENU+EHB+Ltz). Group III also received intramuscular injections of MPA (medroxy progesterone acetate) every four weeks, while group IV received oral doses of Ltz daily. At the end of 16 weeks, the animals were sacrificed, and blood samples were collected for the measurement of serum estradiol and progesterone levels. Uterine histological sections were made to evaluate the presence of endometrial proliferative lesions. Differences between groups were evaluated with student's t test, ANOVA and chi-square test. RESULTS: Groups ENU+EHB, ENU+EHB+MPA and ENU+EHB+Ltz showed varying degrees of endometrial hyperplasia. The incidence of hyperplasia in groups ENU+EHB and ENU+EHB+Ltz was higher and more severe than in group ENU+EHB+MPA. Control group showed lower levels of serum estradiol than the other groups. CONCLUSION: There was no evidence that letrozole could act as an antiestrogenic drug in the development of endometrial proliferative lesions.
Asunto(s)
Animales , Femenino , Triazoles/farmacología , Inhibidores de la Aromatasa/farmacología , Hiperplasia Endometrial/tratamiento farmacológico , Carcinogénesis/efectos de los fármacos , Nitrilos/farmacología , Progesterona/sangre , Factores de Tiempo , Triazoles/uso terapéutico , Adenocarcinoma/etiología , Adenocarcinoma/tratamiento farmacológico , Reproducibilidad de los Resultados , Resultado del Tratamiento , Neoplasias Endometriales/etiología , Neoplasias Endometriales/tratamiento farmacológico , Acetato de Medroxiprogesterona/farmacología , Antineoplásicos Hormonales/farmacología , Inhibidores de la Aromatasa/uso terapéutico , Hiperplasia Endometrial/inducido químicamente , Hiperplasia Endometrial/patología , Endometrio/efectos de los fármacos , Endometrio/patología , Estradiol/sangre , Etilnitrosourea , Carcinogénesis/patología , Ratones Endogámicos BALB C , Nitrilos/uso terapéuticoRESUMEN
BACKGROUND: Many clinical trials have shown the efficacy of aromatase inhibitors (AIs) in the management of breast cancer (BC). There is growing evidence that CYP19A1 single-nucleotide polymorphisms (SNPs) are associated with clinical response (CR) and adverse effects (AEs) among BC patients treated with AIs. The aim of this study was to analyze the association between CYP19A1 polymorphisms and AI treatment in BC patients. METHODS: A systematic review was performed in MEDLINE, EMBASE, and LILACS. A meta-analysis was conducted to compare the association between CYP19A1 variants and treatment response among BC patients. RESULTS: A total of 12 studies were included in the final analysis. There was significant variation among the populations studied and the SNPs and outcomes investigated. A meta-analysis was only possible for the evaluation of SNP rs4646 vs. the wild-type variant with respect to time to progression (TTP) among metastatic BC patients treated with AI. TTP was significantly increased in patients with the rs4646 variant compared with the wild-type gene (hazard ratio (HR) = 0.51 [95 % confidence interval (CI), 0.33-0.78], P = 0.002). Seven studies analyzed the association between AEs with different polymorphisms of CYP19A1. Although there was a statistically significant association with musculoskeletal adverse events (rs934635, rs60271534, rs700518rs, and haplotype M_3_5) and with vasomotor symptoms (rs934635, rs1694189, rs7176005, and haplotype M_5_3) in individual studies, similar associations were not observed in further studies. No statistically significant association between musculoskeletal AEs and SNPs rs4646, rs10046, rs727479, and rs1062033 was found. CONCLUSIONS: These findings suggest that the presence of the rs4646 variant may be a predictive factor of the benefit of AI treatment for BC. The effects of CYP19A1 polymorphisms on clinical outcomes were most often detected in individual studies, suggesting that longer-term studies will better clarify these associations. Additional studies are needed to clarify the predictive value of other SNPs and whether CYP19A1 genotyping should be used to guide AI treatment.
Asunto(s)
Inhibidores de la Aromatasa/farmacología , Aromatasa/genética , Neoplasias de la Mama , Resistencia a Antineoplásicos/genética , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Biomarcadores de Tumor/genética , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Femenino , Pruebas Genéticas , Haplotipos , Humanos , Farmacogenética , Polimorfismo de Nucleótido Simple , Valor Predictivo de las Pruebas , PronósticoRESUMEN
Two experiments were performed using the aromatase inhibitor (AI) letrozole (100mg/kg) to promote sex change, from female-to-male, in protogynous dusky grouper. One experiment was performed during the breeding season (spring) and the other at the end of the breeding season (summer). During the spring, AI promoted sex change after 9 weeks and the sperm produced was able to fertilize grouper oocytes. During the summer, the sex change was incomplete; intersex individuals were present and sperm was not released by any of the animals. Sex changed gonads had a lamellar architecture; cysts of spermatocytes and spermatozoa in the lumen of the germinal compartment. In the spring, after 4 weeks, 11ketotestosterone (11KT) levels were higher in the AI than in control fish, and after 9 weeks, coincident with semen release, testosterone levels increased in the AI group, while 11KT returned to the initial levels. Estradiol (E2) levels remained unchanged during the experimental period. Instead of decreasing throughout the period, as in control group, 17 α-OH progesterone levels did not change in the AI-treated fish, resulting in higher values after 9 weeks when compared with control fish. fshß and lhß gene expression in the AI animals were lower compared with control fish after 9 weeks. The use of AI was effective to obtain functional males during the breeding season. The increase in androgens, modulated by gonadotropins, triggered the sex change, enabling the development of male germ cells, whereas a decrease in E2 levels was not required to change sex in dusky grouper.
Asunto(s)
Inhibidores de la Aromatasa/farmacología , Hormonas Esteroides Gonadales/metabolismo , Gonadotropinas Hipofisarias/metabolismo , Gónadas/efectos de los fármacos , Gónadas/metabolismo , Animales , Cruzamiento , Femenino , MasculinoRESUMEN
Chrysin is one of the natural flavonoids present in plants, and large amounts are present in honey and propolis. In addition to anticancer, antioxidation, and anti-inflammatory activities, chrysin has also been reported to be an inhibitor of aromatase, an enzyme converting testosterone into estrogen. The present study evaluated the mutagenicity of this flavonoid using micronucleus (MN) with HepG2 cells and Salmonella. Cell survival after exposure to different concentrations of chrysin was also determined using sulforhodamine B (SRB) colorimetric assay in HepG2 cells and the influence of this flavonoid on growth of cells in relation to the cell cycle and apoptosis. The MN test showed that from 1 to 15 µM of this flavonoid mutagenic activity was noted in HepG2 cells. The Salmonella assay demonstrated a positive response to the TA100 Salmonella strain in the presence or absence of S9, suggesting that this compound acted on DNA, inducing base pair substitution before or after metabolism via cytochrome P-450. The SRB assay illustrated that chrysin promoted growth inhibition of HepG2 cells in both periods studied (24 and 48 h). After 24 h of exposure it was noted that the most significant results were obtained with a concentration of 50 µM, resulting in 83% inhibition and SubG0 percentage of 12%. After 48 h of incubation cell proliferation inhibition rates (97% at 50 µM) were significantly higher. Our results showed that chrysin is a mutagenic and cytotoxic compound in cultured human HepG2 cells and Salmonella typhimurium. Although it is widely accepted that flavonoids are substances beneficial to health, one must evaluate the risk versus benefit relationship and concentrations of these substances to which an individual may be exposed.
Asunto(s)
Inhibidores de la Aromatasa/farmacología , Flavonoides/farmacología , Salmonella/efectos de los fármacos , Ciclo Celular , Proliferación Celular/efectos de los fármacos , Estradiol/química , Estradiol/metabolismo , Células Hep G2 , Hepatocitos/efectos de los fármacos , Hepatocitos/enzimología , Humanos , Pruebas de Micronúcleos , Estructura Molecular , Mutagénesis , Testosterona/química , Testosterona/metabolismoRESUMEN
In this work we investigated the role of testosterone on cellular processes involved in vascular disease, and whether these effects depend on its local conversion to estradiol. Cultures of rat aortic endothelial and smooth muscle cells in vitro treated with physiological concentrations of testosterone were employed. Testosterone rapidly increased endothelial nitric oxide production. To evaluate whether this non genomic action was dependent on testosterone aromatization we used an aromatase inhibitor. Anastrozole compound did not modify the fast increase in nitric oxide production elicited by testosterone. The hormonal effect was completely blocked by an androgen receptor antagonist (flutamide); meanwhile it wasn't modified by the presence of an estrogen receptor antagonist (ICI182780).The possibility of intracellular estradiol synthesis was ruled out when no differences were found in estradiol measurements performed in culture incubation medium from control and testosterone treated cells. The 5α-reductase inhibitor finasteride partially suppressed the enhancement in nitric oxide production, suggesting that the effect of testosterone was partially due to dihydrotestosterone conversion. Testosterone stimulated muscle cell proliferation independent of local conversion to estradiol. When cellular events that play key roles in vascular disease development were analyzed, testosterone prevented monocyte adhesion to endothelial cells induced by a proinflammatory stimulus (bacterial lipopolysaccharides), and prompted muscle cell migration in presence of a cell motility inducer. In summary, testosterone modulates vascular behavior through its direct action on vascular cells independent of aromatization to estradiol. The cellular actions exhibited by the steroid varied whether cells were under basal or inflammatory conditions.
Asunto(s)
Aorta/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Óxido Nítrico/agonistas , Testosterona/farmacología , Inhibidores de 5-alfa-Reductasa/farmacología , Anastrozol , Antagonistas de Andrógenos/farmacología , Animales , Aorta/citología , Inhibidores de la Aromatasa/farmacología , Adhesión Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células Endoteliales/citología , Células Endoteliales/metabolismo , Estradiol/análogos & derivados , Estradiol/farmacología , Antagonistas de Estrógenos/farmacología , Femenino , Finasterida/farmacología , Flutamida/farmacología , Fulvestrant , Monocitos/citología , Monocitos/efectos de los fármacos , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/metabolismo , Óxido Nítrico/biosíntesis , Nitrilos/farmacología , Ratas , Ratas Wistar , Triazoles/farmacologíaRESUMEN
In this study, we evaluated the effects of obesity and insulin resistance induced by a high-fat diet on prostate morphophysiology, focusing on cell proliferation, expression of androgen (AR) and estrogen receptors (ER) and proteins of the insulin signaling pathway. Adult male Wistar rats were fed a high-fat diet (20% fat) for 15 weeks, whereas control animals received a balanced diet (4% fat). Both groups were then divided and treated for 2 weeks with 1 mg/kg body weight/day of the aromatase inhibitor letrozole or vehicle only. The ventral prostate was analyzed with immunohistochemical, histopathological, stereological, and Western blotting methods. Obese rats showed insulin resistance, hyperinsulinemia, and reduced plasma testosterone levels. The incidence of prostatic intraepithelial neoplasia (PIN) was 2.7 times higher in obese rats and affected 0.4% of the gland compared with 0.1% PIN areas found in control rats. Obesity doubled cell proliferation in both prostate epithelium and stroma. AR content decreased in the prostate of obese rats and estrogen receptor beta (ERß) increased in this group. Protein levels of insulin receptor substrate 1 and protein kinase B diminished in the obese group, whereas phosphatidylinositol 3-kinase (PI3K) increased significantly. Most structural changes observed in the prostate of obese rats normalized after letrozole treatment, except for increased stromal cell proliferation and ERß expression, which might be associated with insulin resistance. This experimental model of obesity and insulin resistance induced by a high-fat diet increases cell proliferation in rat prostate. Such alterations are associated with decreased levels of AR and increased ERß and PI3K proteins. This change can facilitate the establishment of proliferative lesions in rat prostate.
Asunto(s)
Proliferación Celular , Dieta Alta en Grasa , Receptor beta de Estrógeno/metabolismo , Resistencia a la Insulina , Obesidad/etiología , Fosfatidilinositol 3-Quinasa/metabolismo , Próstata/metabolismo , Animales , Inhibidores de la Aromatasa/farmacología , Western Blotting , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Células Epiteliales/metabolismo , Hiperinsulinismo/etiología , Hiperinsulinismo/metabolismo , Inmunohistoquímica , Insulina/metabolismo , Proteínas Sustrato del Receptor de Insulina/metabolismo , Letrozol , Masculino , Nitrilos/farmacología , Obesidad/metabolismo , Obesidad/patología , Obesidad/fisiopatología , Próstata/efectos de los fármacos , Próstata/patología , Neoplasia Intraepitelial Prostática/etiología , Neoplasia Intraepitelial Prostática/metabolismo , Neoplasias de la Próstata/etiología , Neoplasias de la Próstata/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Wistar , Receptores Androgénicos/metabolismo , Transducción de Señal , Células del Estroma/metabolismo , Testosterona/sangre , Factores de Tiempo , Triazoles/farmacologíaRESUMEN
Men living at high altitudes in Peru compared to sea level counterparts have erythrocytosis (hemoglobin 16-21 g/dl) or excessive erythrocytosis (hemoglobin>21 g/dl). High testosterone (T) levels in men at high altitude (HA) were associated with excessive erythrocytosis. High androgen levels could be due to a low aromatase activity or to an elevated rate of conversion from precursors to testosterone. The aim of this study was to evaluate aromatase activity and rate of conversion from precursors to testosterone before and after administration of the aromatase enzyme inhibitor letrozole (5 mg/day) for a 5-day period to men at HA and at sea level (SL). The response to short term aromatase inhibition was assessed in 30 adult men living at sea level, 31 native men at HA with erythrocytosis (Hb 16-21 g/dl), and 35 men at HA with excessive erythrocytosis (Hb>21 g/dl). Serum hormone levels, estradiol/testosterone, testosterone/androstenedione, and testosterone/dehydroepiandrosterone sulfate (DHEAS) ratios were measured. Men with erythrocytosis had lower basal serum T/androstenedione ratios than men with excessive erythrocytosis at HA and men at sea level. Men at HA with excessive erythrocytosis had higher T/DHEAS ratios than men with erythrocytosis and than those at sea level before and after letrozole administration. After letrozole administration, both groups of men at high altitude (with erythrocytosis or with excessive erythrocytosis) showed lower aromatase activities than those at sea level. In conclusion, higher serum testosterone levels in men with excessive erythrocytosis were associated with an increased rate of conversion from DHEAS to testosterone rather than to a lower aromatase activity.
Asunto(s)
Altitud , Inhibidores de la Aromatasa/farmacología , Aromatasa/sangre , Sulfato de Deshidroepiandrosterona/sangre , Nitrilos/farmacología , Policitemia/sangre , Testosterona/sangre , Triazoles/farmacología , Adulto , Androstenodiona/sangre , Estudios de Cohortes , Estradiol/sangre , Hemoglobinas/metabolismo , Humanos , Letrozol , Masculino , Persona de Mediana Edad , Oximetría , Perú , Policitemia/enzimología , Estudios Prospectivos , Estadísticas no ParamétricasRESUMEN
INTRODUCTION: Inhibition of phosphatidylinositol-3-kinase (PI3K) induces apoptosis when combined with estrogen deprivation in estrogen receptor (ER)-positive breast cancer. The aims of the present study were to identify effective PI3K pathway inhibitor and endocrine therapy combinations, to evaluate the effect of PI3K pathway mutations and estrogen dependency on tumor response, and to determine the relevance of PIK3CA mutation in recurrent disease. METHODS: The PI3K catalytic subunit inhibitor BKM120, the mammalian target of rapamycin (mTOR) inhibitor RAD001 and the dual PI3K/mTOR inhibitor BGT226 were tested against ER-positive breast cancer cell lines before and after long-term estrogen deprivation (LTED). The impact of estradiol deprivation and the ER downregulator fulvestrant on PI3K pathway inhibitor-induced apoptosis was assessed. PIK3CA hotspot mutation analysis was performed in 51 recurrent or metastatic breast cancers and correlated with ER status and survival. RESULTS: Drug-induced apoptosis was most marked in short-term estrogen-deprived cells with PIK3CA mutation and phosphatase and tensin homolog loss. Apoptosis was most highly induced by BGT226, followed by BKM120, and then RAD001. Estradiol antagonized PI3K inhibitor-induced apoptosis following short-term estrogen deprivation, emphasizing a role for estrogen-deprivation therapy in promoting PI3K inhibitor activity in the first-line setting. ER-positive MCF7 LTED cells exhibited relative resistance to PI3K pathway inhibition that was reversed by fulvestrant. In contrast, T47D LTED cells exhibited ER loss and ER-independent PI3K agent sensitivity. PIK3CA mutation was prevalent in relapsed ER-positive disease (48%) and was associated with persistent ER positivity and a late relapse pattern. CONCLUSIONS: Estrogen deprivation increased the apoptotic effects of PI3K and dual PI3K/mTOR inhibitors in ER-positive disease, providing a rationale for PI3K/aromatase inhibitor combinations as first-line therapy. In LTED cells, differential effects on ER expression may be a relevant consideration. When ER was persistently expressed, fulvestrant strongly promoted PI3K drug activity. When ER was lost, PI3K inhibitor monotherapy was sufficient to induce high-level apoptosis. Although tumors with PIK3CA mutation had a late recurrence pattern, these mutations were common in metastatic disease and were most often associated with persistent ER expression. Targeting PIK3CA mutant tumors with a PI3K pathway inhibitor and fulvestrant is therefore a feasible strategy for aromatase-inhibitor-resistant ER-positive relapsed breast cancer.
Asunto(s)
Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Inhibidores de las Quinasa Fosfoinosítidos-3 , Receptores de Estrógenos/metabolismo , Aminopiridinas/farmacología , Apoptosis/efectos de los fármacos , Inhibidores de la Aromatasa/farmacología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasa Clase I , Estradiol/análogos & derivados , Estradiol/metabolismo , Estradiol/farmacología , Estrógenos/metabolismo , Everolimus , Femenino , Fulvestrant , Humanos , Imidazoles/farmacología , Morfolinas/farmacología , Mutación , Recurrencia Local de Neoplasia/genética , Fosfohidrolasa PTEN/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Quinolinas/farmacología , Transducción de Señal/efectos de los fármacos , Sirolimus/análogos & derivados , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidoresRESUMEN
Testosterone induces vasorelaxation through non-genomic mechanisms in several isolated blood vessels, but no study has reported its effects on the canine basilar artery, an important artery implicated in cerebral vasospasm. Hence, this study has investigated the mechanisms involved in testosterone-induced relaxation of the canine basilar artery. For this purpose, the vasorelaxant effects of testosterone were evaluated in KCl- and/or PGF(2α)-precontracted arterial rings in vitro in the absence or presence of several antagonists/inhibitors/blockers; the effect of testosterone on the contractile responses to CaCl2 was also determined. Testosterone (10-180 µM) produced concentration-dependent relaxations of KCl- or PGF(2α)-precontracted arterial rings which were: (i) unaffected by flutamide (10 µM), DL-aminoglutethimide (10 µM), actinomycin D (10 µM), cycloheximide (10 µM), SQ 22,536 (100 µM) or ODQ (30 µM); and (ii) significantly attenuated by the blockers 4-aminopyridine (K(V); 1 mM), BaCl2 (K(IR); 30 µM), iberiotoxin (BK(Ca²+); 20 nM), but not by glybenclamide (K(ATP); 10 µM). In addition, testosterone (31, 56 and 180 µM) and nifedipine (0.01-1 µM) produced a concentration-dependent blockade of the contraction to CaCl2 (10 µM to 10 mM) in arterial rings depolarized by 60mM KCl. These results, taken together, show that testosterone relaxes the canine basilar artery mainly by blockade of voltage-dependent Ca²+ channels and, to a lesser extent, by activation of K+ channels (K(IR), K(V) and BK(Ca²+)). This effect does not involve genomic mechanisms, production of cAMP/cGMP or the conversion of testosterone to 17ß-estradiol.
Asunto(s)
Arteria Basilar/efectos de los fármacos , Canales de Calcio/metabolismo , Canales de Potasio/metabolismo , Testosterona/farmacología , Vasodilatación , Vasodilatadores/farmacología , 4-Aminopiridina/farmacología , Adenina/análogos & derivados , Adenina/farmacología , Aminoglutetimida/farmacología , Antagonistas de Receptores Androgénicos/farmacología , Animales , Inhibidores de la Aromatasa/farmacología , Compuestos de Bario/farmacología , Arteria Basilar/fisiología , Bloqueadores de los Canales de Calcio/farmacología , Cloruros/farmacología , Cicloheximida/farmacología , Dactinomicina/farmacología , Perros , Inhibidores Enzimáticos/farmacología , Flutamida/farmacología , Técnicas In Vitro , Masculino , Nifedipino/farmacología , Inhibidores de la Síntesis del Ácido Nucleico/farmacología , Oxadiazoles/farmacología , Bloqueadores de los Canales de Potasio/farmacología , Inhibidores de la Síntesis de la Proteína/farmacología , Quinoxalinas/farmacologíaRESUMEN
OBJECTIVE: To evaluate the effect of aromatase inhibitors on ectopic endometrial growth and on the release of proangiogenic and proinflammatory factors in peritoneal fluid (PF). DESIGN: Prospective experimental study. SETTING: Animal research and laboratory facility. ANIMAL(S): Female Balb/c mice 2 months of age. INTERVENTION(S): Mice had surgery performed to induce endometriosis-like lesions. Treatment with anastrozole or letrozole was started on either postoperative day 1 or 28 and continued for 4 weeks. MAIN OUTCOME MEASURE(S): Endometriotic lesions were counted and measured and aromatase expression, cell proliferation, and apoptosis were assessed. Vascular endothelial growth factor (VEGF) and prostaglandin E (PGE) levels were evaluated in the PF. RESULT(S): Endometriosis-like lesions express aromatase P-450. Treatment with either anastrozole or letrozole did not prevent lesion establishment; however, it significantly decreased the size of the endometriotic lesion. When treatment was initiated on postoperative day 1, letrozole and anastrozole decreased cell proliferation and increased apoptosis. When treatment was started on postoperative day 28, both aromatase inhibitors decreased cell proliferation, but only anastrozole augmented apoptosis levels. In addition, letrozole reduced VEGF and PGE levels in PF. Anastrozole diminished VEGF content but did not cause any significant change in PGE levels. CONCLUSION(S): These findings support the further investigation of aromatase inhibition as a treatment option for endometriosis.
Asunto(s)
Inhibidores de la Aromatasa/farmacología , Endometriosis/metabolismo , Nitrilos/farmacología , Triazoles/farmacología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Anastrozol , Animales , Apoptosis/efectos de los fármacos , Aromatasa/biosíntesis , Líquido Ascítico/metabolismo , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Endometriosis/patología , Endometrio/efectos de los fármacos , Femenino , Letrozol , Ratones , Prostaglandinas E/metabolismoRESUMEN
This study compared the efficiency of the aromatase inhibitor, anastrazole, with the antioestrogenic receptor blocker, tamoxifen, on normal (NRL) and hyperplastic prostate glands. Forty healthy dogs were classified as NRL (n = 18) or abnormal (ABN) with benign prostate hyperplasia (n = 22). The dogs were randomly assigned to one of the following six groups, treated for 60 days; oral placebo for normal (NRL-PLC; n = 6) and abnormal (ABN-PLC; n = 6), oral anastrazole 0.25-1 mg/day, for normal (NRL-ANZ, n = 6) and abnormal (ABN-ANZ, n = 8) and oral tamoxifen citrate 2.5-10 mg/day for normal (NRL-TMX; n = 6) and abnormal (ABN-TMX; n = 8) dogs. The dogs were evaluated before treatment and then monthly for 4 months. At the end of the treatment, the prostatic volume decreased by 28.5 +/- 4.3%, 21.6 +/- 6.3% and 0.7 +/- 1.0% in the ABN-TMX, ABN-ANZ and ABN-PLC (p < 0.01), respectively. From then on, prostatic volume began to increase without reaching pre-treatment values at the end of the study. In the ABN animals, there were no differences for this parameter between ANZ and TMX treatment (p > 0.1), whereas in the NRL animals ANZ produced a less pronounced decrease (p < 0.05), libido, testicular consistency and scrotal diameter decreased during treatment in the TMX group (p > 0.05). These parameters and sperm volume, count, motility and morphological abnormalities remained unaltered throughout the study in the ANZ and PLC groups (p > 0.05). There were no haematological nor biochemical side effects. Anastrazole might offer a safe and effective alternative for the medical management of dogs with benign prostatic hyperplasia.
Asunto(s)
Enfermedades de los Perros/tratamiento farmacológico , Nitrilos/farmacología , Próstata/efectos de los fármacos , Hiperplasia Prostática/tratamiento farmacológico , Semen/efectos de los fármacos , Tamoxifeno/farmacología , Triazoles/farmacología , Anastrozol , Animales , Inhibidores de la Aromatasa/farmacología , Perros , Antagonistas de Estrógenos/farmacología , MasculinoRESUMEN
As local steroid metabolism controls the bioavailability of active steroidal hormones in the prostate, the aim of this study, was to investigate the effects of absence of 5-alpha reductase (5alpha-r) and aromatase (Aro) enzymes on prostatic cellular and extracellular components after long-term inhibition. Young, adult and old male Mongolian gerbils were treated orally, once a day, for 30 consecutive days, with Finasteride (10.0 mg/kg) and Letrozole (1.0 mg/kg) (5alpha-r and Aro enzymes inhibitors respectively) simultaneously or separately. Animals were killed on 1, 7, 14 and 21 days post-treatment. Data obtained after double or single enzymatic inhibition with Finasteride and Letrozole demonstrated marked remodelling of epithelial and stromal compartments. During the post-treatment period, particularly on the first and the last analysed days, prostatic epithelial cells showed decreased cytoplasmic volume and secretory activity. In the stroma, collagen fibres had accumulated in the epithelial base and among smooth muscle cells, which showed reduced diameter and condensed cytoplasm, and some of them had a highly irregular external contour. Also in the sub-epithelial area, some fibroblasts acquired an activated phenotype besides increased deposits of amorphous granular material. In conclusion, the inhibition of 5alpha-r and Aro enzymes affected, in a persistent manner, the structural and ultrastructural morphology of the prostate, irrespective of the gerbil's age. Hence these enzymes appear to be crucial in the maintenance of this gland during postnatal development. Also, these data bring more light to the complex issue of the mechanisms of local steroid metabolism and prostatic histology. Thus, the blockade of the steroid-metabolizing enzymes provided an important novel tool to study the relationship between sex steroids and normal physiology and diseases of the prostate.
Asunto(s)
Inhibidores de 5-alfa-Reductasa , Compartimento Celular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Próstata/efectos de los fármacos , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/fisiología , Envejecimiento/metabolismo , Envejecimiento/patología , Animales , Aromatasa/fisiología , Inhibidores de la Aromatasa/farmacología , Peso Corporal/efectos de los fármacos , Compartimento Celular/fisiología , Estradiol/sangre , Finasterida/farmacología , Gerbillinae , Masculino , Microscopía Electrónica , Tamaño de los Órganos/efectos de los fármacos , Próstata/enzimología , Próstata/patología , Próstata/ultraestructura , Testosterona/sangreRESUMEN
OBJECTIVES: Studies have shown that women previously treated for breast cancer present fewer cardiovascular events, indicating a possible protective effect of tamoxifen treatment. The effects of these aromatase inhibitors on cardiovascular protection remain controversial. The aim of this study was to compare some cardiovascular risk markers among breast cancer survivors following treatment with tamoxifen group (TMXg), letrozole group (LTZg) or no endocrine treatment group (NETg). METHODS: A total of 103 breast cancer survivors: 35 using TMXg, 34 using letrozole group (LTZg) and 34 using no endocrine treatment group (NETg) were evaluated. Ultrasonographic evaluation of brachial artery flow-mediated dilation (FMD), carotid intima-media thickness (IMT) and stiffness index (beta); blood total cholesterol, HDL and triglycerides were assessed. RESULTS: All three groups presented similar values of HDL and IMT. TMXg showed the lowest total cholesterol (219.29+/-36.31mg/dL vs. 250.59+/-38.37mg/dL vs. 245.09+/-35.35mg/dL; TMXg vs. LTZg vs. NETg, respectively; p<0.01-ANOVA), the highest triglycerides (139.34+/-41.82mg/dL vs. 111.35+/-28.22mg/dL vs. 122.09+/-33.42mg/dL; p<0.01), the highest FMD (6.32+/-2.33% vs. 4.10+/-2.06% vs. 4.66+/-2.52%; p<0.01) and the lowest stiffness index (beta) (5.08+/-1.68 vs. 6.28+/-1.75 vs. 5.99+/-1.86; p=0.01). LTZg did not differ significantly from NETg on any evaluated parameter. CONCLUSIONS: We did not observe any effect of LTZg on the evaluated cardiovascular risk parameters compared to NETg. As such, the observed difference on lipid values, stiffness index (beta) and FMD between women receiving tamoxifen and letrozole might be best attributed to the beneficial effect of tamoxifen than to a detrimental effect of letrozole.
Asunto(s)
Inhibidores de la Aromatasa/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Endotelio Vascular/efectos de los fármacos , Recurrencia Local de Neoplasia/prevención & control , Nitrilos/farmacología , Tamoxifeno/farmacología , Triazoles/farmacología , Anciano , Arteria Braquial/diagnóstico por imagen , Neoplasias de la Mama/cirugía , Arteria Carótida Externa/diagnóstico por imagen , Estudios de Casos y Controles , Endotelio Vascular/diagnóstico por imagen , Femenino , Humanos , Letrozol , Persona de Mediana Edad , Túnica Íntima/diagnóstico por imagen , Túnica Íntima/efectos de los fármacos , Túnica Media/diagnóstico por imagen , Túnica Media/efectos de los fármacos , Ultrasonografía , Vasodilatación/efectos de los fármacosRESUMEN
Pejerrey is a teleost fish presenting a strong temperature-dependent sex determination. This study was conducted to clone pejerrey amh cDNA, analyze its expression profile during thermal and endocrine manipulation of gonadal differentiation, and compare its expression with that of gonadal aromatase (cyp19a1). Amh displayed higher expression at masculinizing than at feminizing temperatures during the gonadal differentiation period. Its expression at an intermediate temperature (females 1:1 males), was high in half of the larvae and low in the other half. Cyp19a1 showed a reciprocal expression pattern to that of amh both individually- and temperature-wise. Increased cyp19a1 and amh expression was observed before morphological gonadal differentiation. Amh expression in larvae feminized by administration of estradiol or masculinized by the administration of an aromatase inhibitor was down- and up-regulated, respectively. These results show that amh plays a critical role in testicular differentiation and it is apparently modulated by estrogens in this species.