RESUMEN
BACKGROUND: Prior studies indicate that neuroactive steroids mediate some of alcohol's effects. Dutasteride, widely used to treat benign prostatic hypertrophy, is an inhibitor of 5-alpha reductase enzymes, which play a central role in the production of 5α-reduced neuroactive steroids. The purpose of this study was to test dutasteride's tolerability and efficacy for reducing drinking. METHODS: Men (n = 142) with heavy drinking (>24 drinks per week) and a goal to either stop or reduce drinking to nonhazardous levels were randomized to placebo or 1 mg dutasteride daily for 12 weeks. We hypothesized that dutasteride-treated patients would be more successful in reducing drinking. RESULTS: Generalized linear mixed models that included baseline drinking, treatment, time and their 2-way interaction identified significant interactions of treatment-time, such that dutasteride treatment reduced drinking more than placebo. During the last month of treatment, 25% of dutasteride-treated participants had no hazardous drinking (no heavy drinking days and not more than 14 drinks per week) compared with 6% of placebo-treated participants (P = 0.006; NNT = 6). Sensitivity analysis identified baseline drinking to cope as a factor associated with larger reductions in drinking for dutasteride compared with placebo-treated participants. Dutasteride was well tolerated. Adverse events more common in the dutasteride group were stomach discomfort and reduced libido. CONCLUSION: Dutasteride 1 mg daily was efficacious in reducing the number of heavy drinking days and drinks per week in treatment-seeking men. The benefit of dutasteride compared with placebo was greatest for participants with elevated baseline drinking to cope motives.
Asunto(s)
Inhibidores de 5-alfa-Reductasa , Consumo de Bebidas Alcohólicas , Dutasterida , Humanos , Dutasterida/farmacología , Dutasterida/administración & dosificación , Dutasterida/efectos adversos , Masculino , Inhibidores de 5-alfa-Reductasa/farmacología , Inhibidores de 5-alfa-Reductasa/administración & dosificación , Inhibidores de 5-alfa-Reductasa/efectos adversos , Persona de Mediana Edad , Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Adulto , Método Doble Ciego , Resultado del Tratamiento , Anciano , Azaesteroides/farmacología , Azaesteroides/administración & dosificación , Azaesteroides/uso terapéutico , Azaesteroides/efectos adversosRESUMEN
Background: Following the c In the management of BPH, Tamsulosin is an example of a-adrenergic receptor blocker drug that is usually used. In addition, dutasteride is also a BPH drug that works as a group of 5 a reductase inhibitor. However, the weakness of long-term administration of a1-adrenergic receptor antagonists can result in upregulation of prostate smooth muscle cell contractility and expression of a-adrenergic mRNA receptors, resulting in hyperactivity and supersensitivity to a-agonists. Objective: Our study aimed to determine the effect of long-term administration of tamsulosin, dutasteride and tamsulosin-dutasteride combination on the contractility of prostate smooth muscle cells in BPH model rats. Methods: This study was designed using an experimental post test only method, control group design. It measured the contractility of prostate smooth muscle cells from samples obtained from the prostatic stroma of experimental animals adult male Rattus norvegicus Wistar strain induced BPH and administered tamsulosin 1 mg/kg/day, dutasteride 0.5 mg/kg/day, and a combination of continuous administration for 1, 6 and 12 consecutive days. Data were analyzed using one way ANOVA if the data distribution was normal or Kruskall Walis if the data distribution was abnormal. Result: The effect of tamsulosin, dutasteride and the combination of tamsulosin with dutasteride on prostate smooth muscle cell contractility in experimental animals Rattus norvegicus Wistar strain showed that tamsulosin administration for six days, twelve days, and the combination of tamsulosin dutasteride for one day got statistically significant different result (p=0.016; p=0.006; p=0.029) compared to the negative control group. In addition, there was a difference between the tamsulosin and dutasteride combination group for 12 days compared to tamsulosin monotherapy for 6 days and 12 days (p=0.160; p=0.010). Conclusion: Continuous administration of monotherapy tamsulosin has an upregulation effect on the sixth to twelfth day. Decreased contractility of prostate smooth muscle cells occurs on the first day but will increase on the sixth to twelfth day. On the other hand, the results of our study also showed that the combination of tamsulosin and dutasteride gave the effect of reducing contractility and was most effective on day 12.
Asunto(s)
Hiperplasia Prostática , Humanos , Masculino , Animales , Ratas , Dutasterida/farmacología , Dutasterida/uso terapéutico , Tamsulosina/farmacología , Tamsulosina/uso terapéutico , Hiperplasia Prostática/tratamiento farmacológico , Próstata , Inhibidores de 5-alfa-Reductasa/farmacología , Inhibidores de 5-alfa-Reductasa/uso terapéutico , Azaesteroides/farmacología , Azaesteroides/uso terapéutico , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Quimioterapia Combinada , Ratas Wistar , Músculo LisoRESUMEN
BACKGROUND: The incidence of bladder cancer (BCa) is approximately four times higher in men than in women. To develop effective BCa treatments, there is an urgent need to understand the differences in the BCa control mechanisms based on gender. Our recent clinical study showed that androgen suppression therapy using 5α-reductase inhibitors and androgen deprivation therapy affects BCa progression, but the underlying mechanisms are still unknown. METHODS: mRNA expression levels of the androgen receptor (AR) and SLC39A9 (membrane AR) in T24 and J82 BCa cells were evaluated by reverse transcription-PCR (RT-PCR). The effect of dutasteride, a 5α-reductase inhibitor, in BCa progression was determined in cells transfected with control and AR-overexpressing plasmids. In addition, cell viability and migration assays, RT-PCR, and western blot analysis were performed to analyze the effect of dutasteride on BCa in the presence of testosterone. Finally, steroidal 5α-reductase 1 (SRD5A1), one of the dutasteride target genes, was silenced in T24 and J82 BCa cells using control and shRNA-containing plasmids, and the oncogenic role of SRD5A1 was evaluated. RESULTS: Dutasteride treatment led to significant inhibition of the testosterone-induced increase dependent on AR and SLC39A9 in cell viability and migration of T24 and J82 BCa cells and induced alterations in the expression level of cancer progression proteins, such as metalloproteases, p21, BCL-2, NF-KB, and WNT in AR-negative BCa. Furthermore, the bioinformatic analysis showed that mRNA expression levels of SRD5A1 were significantly higher in BCa tissues than in normal paired tissues. A positive correlation between SRD5A1 expression and poor patient survival was observed in patients with BCa. Also, Dutasteride treatment reduced cell proliferation and migration via blocking the SRD5A1 in BCa. CONCLUSIONS: Dutasteride inhibited testosterone-induced BCa progression dependent on SLC39A9 in AR-negative BCa and repressed oncogenic signaling pathways, including those of metalloproteases, p21, BCL-2, NF-KB, and WNT. Our results also suggest that SRD5A1 plays a pro-oncogenic role in BCa. This work provides potential therapeutic targets for the treatment of BCa.
Asunto(s)
Inhibidores de 5-alfa-Reductasa , Neoplasias de la Vejiga Urinaria , Humanos , Inhibidores de 5-alfa-Reductasa/farmacología , Antagonistas de Andrógenos/farmacología , Andrógenos/farmacología , Azaesteroides/farmacología , Dutasterida/farmacología , Hiperplasia/tratamiento farmacológico , Hiperplasia/metabolismo , FN-kappa B/metabolismo , Oxidorreductasas/metabolismo , Próstata/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , ARN Mensajero/metabolismo , Testosterona/metabolismo , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/metabolismo , Línea Celular TumoralRESUMEN
Background: The α-adrenergic receptor antagonist is the most effective medical therapy to reduce the dynamic component in patients with BPH. However, long-term administration of receptor antagonists can cause upregulation of mRNA receptor expression, resulting in tolerance of drug effectiveness. PKC-α is involved in the process of prostate smooth muscle contraction through activation of the voltage-gated Ca2+ conducted canal, influenced by androgen hormones, especially testosterone, and has an isoform with Twist1, a transcription factor that plays a role in up-regulation of androgen receptors. Objective: The aim of the study was to compare the effect of long-term tamsulosin monotherapy and tamsulosin - dutasteride combination therapy in PKC-α enzyme expression in prostate stromal tissue of Rattus norvegicus rats of Wistar strain. Methods: Out of 80 samples of Rattus norvegicus rats were divided into 8 groups with different interventions: negative control group, positive control group, tamsulosin monotherapy administration for 1 day, 3 day, and 6 day groups, and tamsulosin - dutasteride combination therapy for 1 day, 3 day, and 6 day groups. BPH was induced with 3 mg/kg of testosterone proprionate for 3 weeks, continued with drugs administration according to intervention grouping. Prostate stromal tissue was taken and prepared for PKC-α enzyme measurement with ELISA method. Results: There was a significant difference (p<0.05) in the effect of tamsulosin monotherapy and tamsulosin-dutasteride combination therapy on the PKC-α expression. There was a strong positive relationship between the duration of tamsulosin-dutasteride combination therapy on the PKC-α expression, which means the longer the duration of the combination of tamsulosin-dutasteride combination the higher the PKC-α expression. Conclusion: Administration of long-term tamsulosin - dutasteride combination therapy causes upregulation PKC-α expression more than tamsulosin only.
Asunto(s)
Hiperplasia Prostática , Animales , Masculino , Ratas , Inhibidores de 5-alfa-Reductasa/farmacología , Inhibidores de 5-alfa-Reductasa/uso terapéutico , Azaesteroides/farmacología , Azaesteroides/uso terapéutico , Quimioterapia Combinada , Dutasterida/farmacología , Dutasterida/uso terapéutico , Próstata , Hiperplasia Prostática/tratamiento farmacológico , Ratas Wistar , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Tamsulosina/farmacología , Tamsulosina/uso terapéutico , TestosteronaRESUMEN
A series of novel 21E-arylidene-4-azapregn-5-ene steroids has been successfully designed, synthesized and structurally characterized, and their antiproliferative activity was evaluated in four different cell lines. Within this group, the 21E-(pyridin-3-yl)methylidene derivative exhibited significant cytotoxic activity in hormone-dependent cells LNCaP (IC50 = 10.20 µM) and T47-D cells (IC50 = 1.33 µM). In PC-3 androgen-independent cells, the steroid 21E-p-nitrophenylidene-4-azapregn-5-ene was the most potent of this series (IC50 = 3.29 µM). Considering these results, the 21E-(pyridin-3-yl)methylidene derivative was chosen for further biological studies on T47-D and LNCaP cells, and it was shown that this azasteroid seems to lead T47-D cells to apoptotic death. Finally, molecular docking studies were performed to explore the affinity of these 4-azapregnene derivatives to several steroid targets, namely 5α-reductase type 2, estrogen receptor α, androgen receptor and CYP17A1. In general, compounds presented higher affinity to 5α-reductase type 2 and estrogen receptor α.
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Antineoplásicos , Receptores Androgénicos , Andrógenos/farmacología , Antineoplásicos/farmacología , Azaesteroides/farmacología , Línea Celular Tumoral , Proliferación Celular , Colestenona 5 alfa-Reductasa/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Receptor alfa de Estrógeno , Simulación del Acoplamiento Molecular , Estructura Molecular , Receptores Androgénicos/metabolismo , Relación Estructura-ActividadRESUMEN
BACKGROUND/AIM: Curcumin is a natural compound of turmeric, which inhibits prostate cancer cell proliferation. This study examined whether treatment of LNCaP prostate cancer cells with the combination of curcumin and dutasteride, a 5-alpha reductase inhibitor, affect proliferation and the amount of testosterone and dihydrotestosterone. MATERIALS AND METHODS: LNCaP Cells were incubated with curcumin or the combination of curcumin and dutasteride and cell proliferation was measured at 72 h. LC-MS/MS was used to determine testosterone and dihydrotestosterone concentrations in prostate cancer cells. RESULTS: Curcumin combined with dutasteride suppressed proliferation and affected apoptosis of LNCaP cells. The combination of curcumin and dutasteride also reduced the amount of testosterone and dihydrotestosterone in LNCaP cells. The secretion of prostate-specific antigen was inhibited by the combination treatment in a dose-dependent manner. CONCLUSION: Treatment with the combination of curcumin and dutasteride may interfere with the intra-tumoral androgen activity.
Asunto(s)
Curcumina , Neoplasias de la Próstata , Inhibidores de 5-alfa-Reductasa/farmacología , Azaesteroides/farmacología , Línea Celular Tumoral , Cromatografía Liquida , Curcumina/farmacología , Dihidrotestosterona/farmacología , Dutasterida/farmacología , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Espectrometría de Masas en TándemRESUMEN
Inhibitors of enzymes in essential cellular pathways are potent probes to decipher intricate physiological functions of biomolecules. The analysis of Arabidopsis thaliana sterol profiles upon treatment with a series of azasterols reveals a specific in vivo inhibition of SMT2, a plant sterol-C-methyltransferase acting as a branch point between the campesterol and sitosterol biosynthetic segments in the pathway. Side chain azasteroids that modify sitosterol homeostasis help to refine its particular function in plant development.
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Proteínas de Arabidopsis , Arabidopsis/metabolismo , Azaesteroides/farmacología , Inhibidores Enzimáticos/farmacología , Metiltransferasas , Fitosteroles/biosíntesis , Proteínas de Arabidopsis/antagonistas & inhibidores , Proteínas de Arabidopsis/metabolismo , Azaesteroides/química , Inhibidores Enzimáticos/química , Metiltransferasas/antagonistas & inhibidores , Metiltransferasas/metabolismoRESUMEN
Cancer is the second leading cause of death worldwide following cardiovascular diseases. Cancer can be treated by a variety of techniques including surgery, radiation therapy, immunotherapy, and chemotherapy. Choice of the method can be made based on type, physiologic location and the stage of disease progression. Among chemical methods, steroids find broad applications. Azasteroids have N- substitutions in steroidal rings. This structural modification renders azasteroids advantageous in increased effectiveness and reduced side effects. Numerous accounts of cancer efficacy of this family of compounds are available in literature. The progress made in the discovery, synthetic efforts and development of azasteroids as anticancer agents is broadly outlined in this review.
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Antineoplásicos/farmacología , Azaesteroides/farmacología , Descubrimiento de Drogas , Neoplasias/tratamiento farmacológico , Antineoplásicos/síntesis química , Antineoplásicos/química , Azaesteroides/síntesis química , Azaesteroides/química , Proliferación Celular/efectos de los fármacos , Humanos , Neoplasias/patologíaRESUMEN
One-third of the world's population carries Mycobacterium tuberculosis (Mtb), the infectious agent that causes tuberculosis (TB), and every 17 s someone dies of TB. After infection, Mtb can live dormant for decades in a granuloma structure arising from the host immune response, and cholesterol is important for this persistence of Mtb. Current treatments require long-duration drug regimens with many associated toxicities, which are compounded by the high doses required. We phenotypically screened 35 6-azasteroid analogues against Mtb and found that, at low micromolar concentrations, a subset of the analogues sensitized Mtb to multiple TB drugs. Two analogues were selected for further study to characterize the bactericidal activity of bedaquiline and isoniazid under normoxic and low-oxygen conditions. These two 6-azasteroids showed strong synergy with bedaquiline (fractional inhibitory concentration index = 0.21, bedaquiline minimal inhibitory concentration = 16 nM at 1 µM 6-azasteroid). The rate at which spontaneous resistance to one of the 6-azasteroids arose in the presence of bedaquiline was approximately 10-9, and the 6-azasteroid-resistant mutants retained their isoniazid and bedaquiline sensitivity. Genes in the cholesterol-regulated Mce3R regulon were required for 6-azasteroid activity, whereas genes in the cholesterol catabolism pathway were not. Expression of a subset of Mce3R genes was down-regulated upon 6-azasteroid treatment. The Mce3R regulon is implicated in stress resistance and is absent in saprophytic mycobacteria. This regulon encodes a cholesterol-regulated stress-resistance pathway that we conclude is important for pathogenesis and contributes to drug tolerance, and this pathway is vulnerable to small-molecule targeting in live mycobacteria.
Asunto(s)
Antituberculosos/farmacología , Azaesteroides/farmacología , Proteínas Bacterianas/genética , Mycobacterium tuberculosis/efectos de los fármacos , Antituberculosos/química , Azaesteroides/química , Proteínas Bacterianas/efectos de los fármacos , Diarilquinolinas/química , Diarilquinolinas/farmacología , Regulación hacia Abajo , Farmacorresistencia Bacteriana/efectos de los fármacos , Sinergismo Farmacológico , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Isoniazida/química , Isoniazida/farmacología , Estructura Molecular , Mycobacterium tuberculosis/genética , Regulón , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-ActividadRESUMEN
Breast cancer cell proliferation is promoted by a variety of mitogenic signals. Classically estrogen is considered as most predominant mitogenic signal in hormone-dependent breast cancer and progesterone is primarily considered to have protective effect. However, it is suggested that some progesterone metabolite may promote breast cancer and progesterone metabolites like 5α-pregnane and 4-pregnene could serve as regulators of estrogen-responsiveness of breast cancer cells. Here, we estimated the potential of alternate targeting of breast cancer via progesterone signalling. l-Proline derived novel 14-azasteroid compounds were screened against MCF-7 and MDA-MB-231 cell lines using MTT assay. In silico studies, cell cycle, Annexin-V-FITC/PI, JC-1 mitochondrial assay, ROS analysis were performed to analyse the impact of hit compound 3b on breast cancer cells. Further, we analysed the impact of hit 3b on the progesterone, its metabolites and enzymes responsible for the conversion of progesterone and its metabolites using ELISA. Data suggests that compound 3b binds and down regulates of 5α-reductase by specifically inhibiting production of progesterone metabolites that are capable of promoting breast cancer proliferation, epithelial mesenchymal transition and migration. This study establishes the proof of concept and generation of new leads for additional targeting of breast cancer.
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Antineoplásicos/farmacología , Azaesteroides/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Progesterona/antagonistas & inhibidores , Prolina/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Azaesteroides/síntesis química , Azaesteroides/química , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Células MCF-7 , Modelos Moleculares , Estructura Molecular , Progesterona/metabolismo , Prolina/química , Relación Estructura-ActividadRESUMEN
The androgen receptor (AR) is a member of the nuclear hormone receptor super family of transcription factors. Androgens play an essential role in the development, growth, and maintenance of male sex organs, as well as the musculoskeletal and central nervous systems. Yet with advancing age, androgens can drive the onset of prostate cancer, the second leading cause of cancer death in males within the United States. Androgen deprivation therapy (ADT) by pharmacologic and/or surgical castration induces apoptosis of prostate cells and subsequent shrinkage of the prostate and prostate tumors. However, ADT is associated with significant musculoskeletal and behavioral adverse effects. The unique pharmacological activity of selective androgen receptor modulator (SARM) MK-4541 recently has been reported as an AR antagonist with 5α-reductase inhibitor function. The molecule inhibits proliferation and induces apoptosis in AR positive, androgen dependent prostate cancer cells. Importantly, MK-4541 inhibited androgen-dependent prostate growth in male rats yet maintained lean body mass and bone formation following ovariectomy in female rats. In the present study, we evaluated the effects of SARM MK-4541 in the androgen-dependent Dunning R3327-G prostate carcinoma xenograft mouse model as well as on skeletal muscle mass and function, and AR-regulated behavior in mice. MK-4541 significantly inhibited the growth of R3327-G prostate tumors, exhibited anti-androgen effects on the seminal vesicles, reduced plasma testosterone concentrations in intact males, and inhibited Ki67 expression. MK-4541 treated xenografts appeared similar to xenografts in castrated mice. Importantly, we demonstrate that MK-4541 exhibited anabolic activity in androgen deficient conditions, increasing lean body mass and muscle function in adult castrated mice. Moreover, MK-4541 treatment restored general activity levels in castrated mice. Thus, MK-4541 exhibits an optimum profile as an adjuvant therapy to ADT which may provide potent anti-androgenic activity at the prostate yet protective activity on skeletal muscle and behavior in patients.
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Anabolizantes/farmacología , Antagonistas de Andrógenos/farmacología , Antineoplásicos/farmacología , Azaesteroides/farmacología , Carbamatos/farmacología , Carcinoma/tratamiento farmacológico , Músculo Esquelético/efectos de los fármacos , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/patología , Quimioterapia Adyuvante/métodos , Humanos , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Ratones , Músculo Esquelético/metabolismo , Orquiectomía , Próstata/efectos de los fármacos , Próstata/metabolismo , Próstata/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Testosterona/antagonistas & inhibidores , Testosterona/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: To clarify the possible interference of the 5α-reductase inhibitor dutasteride with α-adrenergic blockers, whose action is mainly mediated by α1A-adrenergic receptor. METHODS: Male rats were divided into dutasteride and vehicle-treated groups. The drug treatment group was treated with oral dutasteride 0.5 mg/kg/d, and the control group received vehicle only for 2 months. After the 2-month treatment, the rats' ventral prostate weight changes and the testosterone and dihydrotestosterone levels in the serum were measured. In vitro organ-bath studies, real-time polymerase chain reaction, and tissue-segment binding were performed to determine the expression of α1A-adrenergic receptors and its mediated contractility. RESULTS: Dutasteride treatment significantly decreased the rats' ventral prostate weight, increased their testosterone levels, and decreased the dihydrotestosterone levels in their serum. There were no marked changes in the α1A-adrenergic receptor messenger ribonucleic acid expression, relative phenylephrine-induced contractility, or nerve-mediated contractility between the groups. Dutasteride treatment caused no marked changes in the relative binding capacity of α1A-adrenergic receptor, whereas it greatly decreased the total protein expression of this subtype and its mediated maximal contraction in the whole ventral prostate. CONCLUSION: These results suggest that dutasteride does not interfere with α-adrenergic blockers but otherwise has beneficial effects on their actions. Therefore, the long-term administration of the combination of dutasteride with an α-adrenergic blocker might be a better choice for the treatment of lower urinary tract symptoms due to benign prostatic hyperplasia.
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Inhibidores de 5-alfa-Reductasa/farmacología , Azaesteroides/farmacología , Contracción Muscular/efectos de los fármacos , Próstata/efectos de los fármacos , Próstata/fisiología , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Animales , Dutasterida , Masculino , Contracción Muscular/fisiología , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos alfa 1/fisiologíaAsunto(s)
3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/metabolismo , Inhibidores de 5-alfa-Reductasa/farmacología , Azaesteroides/farmacología , Pregnanos/farmacología , Relación Estructura-Actividad Cuantitativa , Inhibidores de 5-alfa-Reductasa/química , Azaesteroides/química , Humanos , Conformación Molecular , Pregnanos/químicaRESUMEN
OBJECTIVE: To explore the molecular mechanism of dutasteride inhibiting fertility by studying its effects on the expressions of the epididymal epithelial junction proteins Claudin1 and ß-catenin in rats. METHODS: Sixteen 3-month-old SD male rats were equally divided into an experimental and a negative control group to be treated intragastrically with dutasteride at 40 mg/kg per day and the same dose of solvent, respectively, for 14 consecutive days. Then, the sperm motility and morphology of the rats were detected by computer-assisted sperm analysis, the serum levels of testosterone (T) and dihydrotestosterone (DHT) measured by ELISA, changes in the tight junction of epididymal cells observed under the transmission electron microscope, the protein and gene expressions of Claudin1 and ß-catenin determined by RT-PCR and immunohistochemistry, and the conception rate of the mated female rats calculated. RESULTS: Dutasteride significantly suppressed the serum DHT level, sperm motility, and fertility of the rats (P <0.05). Interspaces between epididymal epithelial cell tight junctions were observed, the volume of epididymal fluid obviously increased, and the expressions of Claudin1 and ß-catenin gene and protein remarkably downregulated in the experimental rats (P <0.05). CONCLUSION: Dutasteride can significantly inhibit the fertility of male rats by reducing the serum DHT level, suppressing Claudin1 and ß-catenin expressions, and damaging epididymal epithelial cell junctions.
Asunto(s)
Azaesteroides/farmacología , Claudina-1/metabolismo , Epidídimo/efectos de los fármacos , Agentes Urológicos/farmacología , beta Catenina/metabolismo , Animales , Dihidrotestosterona/sangre , Dutasterida , Epidídimo/metabolismo , Femenino , Fertilidad/efectos de los fármacos , Humanos , Uniones Intercelulares/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley , Motilidad Espermática/efectos de los fármacos , Testosterona/sangreRESUMEN
Steroidal 5α-reductase, a key enzyme involved in the transformation of testosterone to dihydrotestosterone, is unstable during the purification leading to loss of the activity. Therefore, due to unstable nature, the crystal structure of the 5α-reductase is unknown. In the present study, we have generated a comparative pharmacophoric model for both isoforms of steroidal 5α-reductase using 6-azasteroids. The steric and electrostatic maps generated for both isoforms provides structure framework for designing of new inhibitors. Further, 3D-maps are also helpful in understanding variability in the activity of the compounds. Statistical measures generated for both enzymes showed good internal and external prediction. Overall, the analyses of models provides structural requirement of dual and selective steroidal 5α-reductase inhibitors in an interactive fashion.
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3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/metabolismo , Inhibidores de 5-alfa-Reductasa/química , Inhibidores de 5-alfa-Reductasa/farmacología , Azaesteroides/química , Azaesteroides/farmacología , Modelos Moleculares , Relación Estructura-Actividad Cuantitativa , Conformación Molecular , Electricidad EstáticaRESUMEN
Benign prostatic hyperplasia and prostate cancer can be treated with the 5α-reductase inhibitors, finasteride and dutasteride, when pharmacodynamic biomarkers are useful in assessing response. A novel method was developed to measure the substrates and products of 5α-reductases (testosterone, 5α-dihydrotestosterone (DHT), androstenedione) and finasteride and dutasteride simultaneously by liquid chromatography tandem mass spectrometry, using an ABSciex QTRAP(®) 5500, with a Waters Acquity™ UPLC. Analytes were extracted from serum (500 µL) via solid-phase extraction (Oasis(®) HLB), with (13)C3-labelled androgens and d9-finasteride included as internal standards. Analytes were separated on a Kinetex C18 column (150 × 3 mm, 2.6 µm), using a gradient run of 19 min. Temporal resolution of analytes from naturally occurring isomers and mass +2 isotopomers was ensured. Protonated molecular ions were detected in atmospheric pressure chemical ionisation mode and source conditions optimised for DHT, the least abundant analyte. Multiple reaction monitoring was performed as follows: testosterone (m/z 289 â 97), DHT (m/z 291 â 255), androstenedione (m/z 287 â 97), dutasteride (m/z 529 â 461), finasteride (m/z 373 â 317). Validation parameters (intra- and inter-assay precision and accuracy, linearity, limits of quantitation) were within acceptable ranges and biological extracts were stable for 28 days. Finally the method was employed in men treated with finasteride or dutasteride; levels of DHT were lowered by both drugs and furthermore the substrate concentrations increased.
Asunto(s)
Inhibidores de 5-alfa-Reductasa/sangre , Andrógenos/sangre , Cromatografía Liquida/métodos , Neoplasias de la Próstata/sangre , Espectrometría de Masas en Tándem/métodos , Inhibidores de 5-alfa-Reductasa/farmacocinética , Inhibidores de 5-alfa-Reductasa/farmacología , Andrógenos/farmacocinética , Andrógenos/farmacología , Androstenodiona/sangre , Androstenodiona/farmacocinética , Androstenodiona/farmacología , Azaesteroides/sangre , Azaesteroides/farmacocinética , Azaesteroides/farmacología , Dihidrotestosterona/sangre , Dihidrotestosterona/farmacocinética , Dihidrotestosterona/farmacología , Dutasterida , Finasterida/sangre , Finasterida/farmacocinética , Finasterida/farmacología , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Extracción en Fase Sólida/métodos , Testosterona/sangre , Testosterona/farmacocinética , Testosterona/farmacología , Distribución TisularRESUMEN
BACKGROUND: Triple negative breast cancer (TNBC) is characterized by lack of expression of both estrogen and progesterone receptor as well as lack of amplification of HER2. Patients with TNBC carry an unfavorable prognosis compared to other breast cancer subtypes given that endocrine or HER2 targeted therapies are not effective, rendering chemotherapy the sole effective treatment option to date. Therefore, there is a high demand for additional novel treatment options. FINDINGS: We previously published a list of genes showing both higher gene expression rates in TNBC and, in addition, are known to encode targets of non-oncologic drugs. SRD5A1, which encodes the type-1 isoform of the steroid-5alpha-reductase, which is involved in androgen metabolism, was found to be one of these genes. Dutasteride is a dual blocker of both the type-1 and type-2 isoform of SRD5A1 and is indicated in the treatment of benign prostate hyperplasia. Treatment of TNBC cell lines with dutasteride was associated with a dose-dependent decrease in cell viability, altered protein expression of VEGF and HIF-1α and increased chemosensitivity. CONCLUSION: Our results demonstrate that the SRD5A1-corresponding anti-androgenic drug dutasteride might act as a combinatorial therapeutic option besides standard chemotherapy in highly aggressive TNBC.
Asunto(s)
Antagonistas de Andrógenos/farmacología , Azaesteroides/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Factor A de Crecimiento Endotelial Vascular/metabolismo , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/genética , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Dutasterida , Femenino , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Transducción de Señal/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
PURPOSE: Dihydrotestosterone is the main active androgen in the prostate and it has a role in prostate cancer progression. After androgen deprivation therapy androgen receptor signaling is still active in tumor cells. Persistent intratumor steroidogenesis and androgen receptor changes are responsible for this continued activity, which influences the efficacy of prostate cancer treatment. We hypothesized that combining a 5α-reductase inhibitor and an antiandrogen would block intratumor androgen synthesis and androgen receptor protein activity. Thus, it would act synergistically to reduce tumor cell proliferation. MATERIALS AND METHODS: The expression level of 5α-reductase and androgen receptor in endocrine therapy naïve prostate cancer and castration resistant prostate cancer tissues, and cell line models was determined by microarray and quantitative polymerase chain reaction analysis. Intracellular androgen was measured with radioimmunoassay. Tumor cell proliferation was determined using coloric MTT assay. The synergistic effects of combination treatments on tumor cell proliferation were calculated using the Chou-Talalay equation. RESULTS: In all prostate cancer cases 5α-reductase-1 and 3 were up-regulated. Androgen receptor was up-regulated in metastatic prostate cancer and castration resistant prostate cancer cases. The 5α-reductase inhibitor dutasteride effectively decreased dihydrotestosterone production in prostate cancer and castration resistant prostate cancer cell lines. Furthermore, dutasteride combined with the novel antiandrogen enzalutamide synergistically suppressed endocrine therapy naïve prostate cancer and castration resistant prostate cancer cell proliferation. CONCLUSIONS: In this study the combination of a 5α-reductase inhibitor and (novel) antiandrogens synergistically inhibited tumor cell proliferation. These findings support clinical studies of combinations of a 5α-reductase inhibitor and (novel) antiandrogens as first line treatment of prostate cancer and castration resistant prostate cancer.
Asunto(s)
Inhibidores de 5-alfa-Reductasa/farmacología , Azaesteroides/farmacología , Proliferación Celular/efectos de los fármacos , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata/patología , Benzamidas , Sinergismo Farmacológico , Quimioterapia Combinada , Dutasterida , Humanos , Masculino , Nitrilos , Feniltiohidantoína/farmacología , Células Tumorales CultivadasRESUMEN
BACKGROUND: Dimethylamylamine (DMAA) is a component of many dietary supplements and has recently been associated with numerous adverse effects, prompting the US military and World Anti-Doping Agency to ban its use as a supplement. The current study aimed to elucidate the abuse liability profile of DMAA. METHODS: Dose-response studies of DMAA were performed with Swiss-Webster mice in locomotor and conditioned place-preference assays. The discriminative stimulus effects of DMAA were investigated in Sprague-Dawley rats trained to discriminate either cocaine or methamphetamine from saline. RESULTS: DMAA produced dose-dependent locomotor depression and fully substituted for cocaine and partially substituted for methamphetamine. In the conditioned place-preference assay, DMAA produced an inverted-U-shaped dose-response curve, with intermediate doses producing significant place preference. CONCLUSIONS: The cocaine- and methamphetamine-like discriminative stimulus effects and the conditioned place preference produced by DMAA suggest that is has potential for abuse. These findings in combination with reports of substantial adverse effects of DMAA in humans suggest that control of DMAA may warrant further consideration.