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1.
Int J Cancer ; 146(1): 123-136, 2020 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-31090219

RESUMEN

Triple-negative breast cancer (TNBCs) is a very aggressive and lethal form of breast cancer with no effective targeted therapy. Neoadjuvant chemotherapies and radiotherapy remains a mainstay of treatment with only 25-30% of TNBC patients responding. Thus, there is an unmet clinical need to develop novel therapeutic strategies for TNBCs. TNBC cells have increased intracellular oxidative stress and suppressed glutathione, a major antioxidant system, but still, are protected against higher oxidative stress. We screened a panel of antioxidant genes using the TCGA and METABRIC databases and found that expression of the thioredoxin pathway genes is significantly upregulated in TNBC patients compared to non-TNBC patients and is correlated with adverse survival outcomes. Treatment with auranofin (AF), an FDA-approved thioredoxin reductase inhibitor caused specific cell death and impaired the growth of TNBC cells grown as spheroids. Furthermore, AF treatment exerted a significant in vivo antitumor activity in multiple TNBC models including the syngeneic 4T1.2 model, MDA-MB-231 xenograft and patient-derived tumor xenograft by inhibiting thioredoxin redox activity. We, for the first time, showed that AF increased CD8+Ve T-cell tumor infiltration in vivo and upregulated immune checkpoint PD-L1 expression in an ERK1/2-MYC-dependent manner. Moreover, combination of AF with anti-PD-L1 antibody synergistically impaired the growth of 4T1.2 primary tumors. Our data provide a novel therapeutic strategy using AF in combination with anti-PD-L1 antibody that warrants further clinical investigation for TNBC patients.


Asunto(s)
Anticuerpos/uso terapéutico , Auranofina/uso terapéutico , Antígeno B7-H1/inmunología , Inhibidores Enzimáticos/uso terapéutico , Reductasa de Tiorredoxina-Disulfuro/antagonistas & inhibidores , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Auranofina/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Especies Reactivas de Oxígeno/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Oxid Med Cell Longev ; 2019: 3503912, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31275508

RESUMEN

Osteoporosis is a degenerative metabolic disease caused by an imbalance between osteogenesis and osteoclastogenesis. Increased levels of proinflammatory cytokines combined with decreased estrogen levels, which are commonly seen in postmenopausal women, can lead to overactivation of osteoclasts. Therefore, targeting osteoclast maturation may represent a novel strategy for both treating and preventing osteoporosis. Auranofin is a gold-based compound first approved in 1985 for the treatment of rheumatic diseases. Here, we examined whether auranofin suppresses osteoclast differentiation in vitro and in vivo. Auranofin was shown to suppress receptor activator of NF-κB ligand- (RANKL-) induced osteoclastogenesis in mouse bone marrow macrophages (BMMs) and Raw264.7 macrophages. Cotreatment of macrophages with auranofin blocked the RANKL-induced inhibitors of κB kinase (IKK) phosphorylation, resulting in inhibition of nuclear translocation of p65. The pan-caspase inhibitor nivocasan potently reduced not only inflammasome-mediated interleukin-1ß (IL-1ß) secretion but also osteoclast differentiation in BMMs. Auranofin suppressed inflammasome activation, as evidenced by decreased production of cleaved IL-1ß in both bone marrow-derived macrophages (BMDMs) and J774.A1 cells. Loss of both bone mass in ovariectomized mice was significantly recovered by oral administration of auranofin. Taken together, these data strongly support the use of auranofin for the prevention of osteoclast-related osteoporosis.


Asunto(s)
Antirreumáticos/uso terapéutico , Auranofina/uso terapéutico , Inflamasomas/metabolismo , FN-kappa B/metabolismo , Osteoclastos/metabolismo , Osteoporosis/tratamiento farmacológico , Animales , Antirreumáticos/farmacología , Auranofina/farmacología , Femenino , Humanos , Ratones , Osteoclastos/citología , Osteoporosis/genética , Osteoporosis/patología , Transfección
3.
Eur J Pharmacol ; 846: 1-11, 2019 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-30639309

RESUMEN

Auranofin (Aur) inhibits thioredoxin reductases and is also an inhibitor of 19S proteasome associated deubiquitinases, targeting USP14 and UCHL5. Androgen receptor is often over-expressed in prostate cancer (PCa) and is strongly linked to PCa growth and progression. Consequently, androgen deprivation therapy (ADT) that reduces androgen has been applied to treat androgen receptor-mediated PCa for decades. Nevertheless, most ADT treated patients experience relapse due to the development of the castration-resistant PCa. Numerous studies have shown that down-regulation of cellular androgen receptor level, including inhibiting its transcription and promoting its protein degradation, is lethal to PCa cells. Here we report that Aur arrested cell cycle progression and induced apoptosis of PCa cells. Co-inhibition of USP14 and UCHL5 with Aur facilitated the ubiquitination and degradation of androgen receptors in LNcap and 22RV1 PCa cells. Our results also show that Aur decreases the mRNA level of androgen receptors. In conclusion, our findings suggest that Aur is a promising agent for clinical translation to treat PCa.


Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Auranofina/farmacología , Neoplasias de la Próstata/enzimología , Receptores Androgénicos/metabolismo , Ubiquitina Tiolesterasa/antagonistas & inhibidores , Antagonistas de Receptores Androgénicos/uso terapéutico , Animales , Apoptosis , Auranofina/uso terapéutico , Línea Celular Tumoral , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones Endogámicos BALB C , Recurrencia Local de Neoplasia , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/enzimología , Transducción de Señal , Ensayos Antitumor por Modelo de Xenoinjerto
4.
BMC Cancer ; 18(1): 522, 2018 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-29724201

RESUMEN

BACKGROUND: The orally available gold complex auranofin (AF) has been used in humans, primarily as an antirheumatic/immunomodulatory agent. It has been safely administered to healthy dogs to establish pharmacokinetic parameters for oral administration, and has also been used as a treatment in some dogs with immune-mediated conditions. Multiple in vitro studies have recently suggested that AF may possess antineoplastic properties. Spontaneous canine lymphoma may be a very useful translational model for the study of human lymphoma, prompting the evaluation of AF in canine lymphoma cells. METHODS: We investigated the antineoplastic activity of AF in 4 canine lymphoid tumor derived cell lines through measurements of proliferation, apoptosis, thioredoxin reductase (TrxR) activity and generation of reactive oxygen species (ROS), and detected the effects of AF when combined with conventional cytotoxic drugs using the Chou and Talalay method. We also evaluated the antiproliferative effects of AF in primary canine lymphoma cells using a bioreductive fluorometric assay. RESULTS: At concentrations that appear clinically achievable in humans, AF demonstrated potent antiproliferative and proapoptotic effects in canine lymphoid tumor cell lines. TrxR inhibition and increased ROS production was observed following AF treatment. Moreover, a synergistic antiproliferative effect was observed when AF was combined with lomustine or doxorubicin. CONCLUSIONS: Auranofin appears to inhibit the growth and initiate apoptosis in canine lymphoma cells in vitro at clinically achievable concentrations. Therefore, this agent has the potential to have near-term benefit for the treatment of canine lymphoma, as well as a translational model for human lymphoma. Decreased TrxR activity and increasing ROS production may be useful biomarkers of drug exposure.


Asunto(s)
Antineoplásicos/farmacología , Auranofina/farmacología , Linfoma/tratamiento farmacológico , Animales , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Auranofina/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Perros , Ensayos de Selección de Medicamentos Antitumorales , Especies Reactivas de Oxígeno/metabolismo , Reductasa de Tiorredoxina-Disulfuro/metabolismo
5.
Sci Rep ; 8(1): 8353, 2018 05 29.
Artículo en Inglés | MEDLINE | ID: mdl-29844350

RESUMEN

Multidrug-resistant enterococcal pathogens, especially vancomycin-resistant enterococci (VRE), are among the pathogens that require new antibiotic innovation. The colonization of the gut represents a major pathway by which VRE can cause infection and spread to other patients. In the current study, auranofin (FDA-approved rheumatoid arthritis drug) is evaluated for its potential use as a decolonizing agent for VRE. Auranofin was found to exert potent antimicrobial activity against a wide range of enterococcal clinical isolates with a minimum inhibitory concentration of 1 µg/mL. No resistant mutants could be developed against auranofin over the course of 14 passages. Auranofin was also found to exert potent anti-biofilm activity against VRE. Auranofin was superior to linezolid, the drug of choice for VRE infection treatment, in the in vivo mouse model. Auranofin significantly reduced the VRE burden in feces, cecum, and ileum contents after 8 days of treatment. Accordingly, this study provides valuable evidence that auranofin has significant promise as a novel gastrointestinal decolonizing agent for VRE.


Asunto(s)
Auranofina/farmacología , Enterococos Resistentes a la Vancomicina/efectos de los fármacos , Animales , Antibacterianos/farmacología , Auranofina/uso terapéutico , Biopelículas/efectos de los fármacos , Reposicionamiento de Medicamentos/métodos , Farmacorresistencia Bacteriana/fisiología , Enterococcus/efectos de los fármacos , Femenino , Intestinos/efectos de los fármacos , Linezolid/farmacología , Ratones , Ratones Endogámicos C57BL , Pruebas de Sensibilidad Microbiana , Vancomicina/farmacología , Resistencia a la Vancomicina/fisiología
6.
Cell Physiol Biochem ; 45(6): 2421-2430, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29554646

RESUMEN

BACKGROUND/AIMS: Cardiac hypertrophy is a major outcome and compensatory response of the cardiovascular system to hemodynamic and additional stress responses that ultimately lead to heart failure. Auranofin (Aur) has been used for treating rheumatic arthritis for several decades. Aur is a 19S proteasome-associated deubiquitinase inhibitor, and inhibition of the proteasome is speculated to reverse cardiac hypertrophy. However, the role of the deubiquitinases, especially 19S proteasome-associated deubiquitinases, in the regulation of cardiac remodeling remains poorly understood. The present study investigated the role of Aur in cardiac hypertrophy both in vitro and in vivo. METHODS: Male Sprague-Dawley rats underwent abdominal aortic constriction to induce left ventricular hypertrophy. The neonatal rat primary myocardial cell hypertrophy model was induced by Ang II. Echocardiography, hematoxylin-eosin staining, Masson's trichrome staining, immunochemistry, western blot analysis, a cell viability assay, and enzyme-linked immunosorbent assay were performed. RESULTS: Aur significantly reduced the abdominal aortic constriction that led to left ventricular hypertrophy, reduced heart cavity expansion, and functional disorder, and thereby reduced fetal gene expression and attenuated cardiac fibrosis. Furthermore, Aur caused marked accumulation of ubiquitinated proteins and IκBα, as well as inactivation of NF-κB. This phenomenon was confirmed in the neonatal rat primary myocardial cell hypertrophy model. CONCLUSIONS: The present study indicated that Aur blocks the development of left ventricular hypertrophy induced by abdominal aortic constriction. This phenomenon might be attributed to inhibition of the 19S proteasome-associated deubiquitinase that can lead to aggregation of IκBα and inactivation of the NF-κB pathway. Thus, Aur could be a potential anti-cardiac hypertrophy agent.


Asunto(s)
Antirreumáticos/uso terapéutico , Auranofina/uso terapéutico , Cardiomegalia/tratamiento farmacológico , Enzimas Desubicuitinizantes/antagonistas & inhibidores , FN-kappa B/antagonistas & inhibidores , Inhibidores de Proteasoma/uso terapéutico , Animales , Antirreumáticos/farmacología , Auranofina/farmacología , Cardiomegalia/metabolismo , Cardiomegalia/patología , Células Cultivadas , Enzimas Desubicuitinizantes/metabolismo , Hipertrofia Ventricular Izquierda , Masculino , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , FN-kappa B/metabolismo , Inhibidores de Proteasoma/farmacología , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos
7.
Free Radic Biol Med ; 115: 405-411, 2018 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-29277393

RESUMEN

The Nrf2 pathway is a biological defense system against oxidative stress. The pharmacological activation of the Nrf2 pathway is a promising therapy for oxidative stress-related diseases, but it has been challenging to find an Nrf2 activator with acceptable toxicity. To circumvent this problem, we focused on an already approved oral anti-arthritic drug, auranofin that has been reported to have the potential to activate Nrf2. We used a zebrafish model to investigate whether auranofin has protective action against oxidative stress in vivo. Auranofin pre-treatment considerably improved the survival of zebrafish larvae that were challenged with a lethal dose of hydrogen peroxide. This protective effect was not observed in an Nrf2 mutant zebrafish strain, suggesting that the activation of the biological defense against oxidative stress was Nrf2-dependent. Auranofin-induced protection was further tested by challenges with redox-active heavy metals. A clear protective effect was observed against arsenite, a highly redox-reactive toxicant. In addition, this effect was also demonstrated to be Nrf2-dependent based on the analysis of an Nrf2 mutant strain. These results clearly demonstrate the anti-oxidative action of auranofin and encourage the repositioning of auranofin as a drug that improves oxidative stress-related pathology.


Asunto(s)
Antioxidantes/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis/tratamiento farmacológico , Auranofina/uso terapéutico , Factor 2 Relacionado con NF-E2/antagonistas & inhibidores , Proteínas de Pez Cebra/antagonistas & inhibidores , Administración Oral , Animales , Antioxidantes/farmacología , Antirreumáticos/farmacología , Arsenitos/toxicidad , Auranofina/farmacología , Modelos Animales de Enfermedad , Reposicionamiento de Medicamentos , Humanos , Peróxido de Hidrógeno/toxicidad , Larva , Metales Pesados/toxicidad , Mutación/genética , Factor 2 Relacionado con NF-E2/genética , Organismos Modificados Genéticamente , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal , Pez Cebra , Proteínas de Pez Cebra/genética
8.
Curr Med Chem ; 23(29): 3374-3403, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27142288

RESUMEN

Gold has always aroused great interest in the history of mankind. It has been used for thousands of years for jewelry, religious cult valuables, durable goods and in the art world. However, few know that such a precious and noble metal was exploited in the past by the ancients also for its therapeutic properties. More recently, in the twentieth century some complexes containing gold centers in the oxidation state +1 were studied for the treatment of the rheumatoid arthritis and the orally-administered drug Auranofin was approved by the FDA in 1985. From the chemical point of view, gold derivatives deserve special attention due to the unique position of this metal within the periodic table, which results in unconventional relativistic effects and, ultimately, in the highest electronegativity, electron affinity and redox potential among all metals. In this review, after an introduction concerning the use of gold complexes in medicine, we have examined all the patents internationally or nationally published in the years 2010-2015 (until December 31, 2015) and describing new inorganic compounds containing gold(I) and gold(III) with proved therapeutic properties. These patents were filed to mainly protect compounds with promising anticancer and anti-inflammatory activities (total 18 and 4, respectively). In particular, this work explores both coordination compounds containing ligands with various donor atoms (e.g., N-, O-, S- and -P) and organo-gold derivatives with at least one Au-C bond. The toxicological profile and the intracellular targets reported for some among the patented gold derivatives are discussed.


Asunto(s)
Complejos de Coordinación/química , Oro/química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Auranofina/química , Auranofina/farmacología , Auranofina/uso terapéutico , Complejos de Coordinación/farmacología , Complejos de Coordinación/uso terapéutico , Humanos , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Patentes como Asunto , Reductasa de Tiorredoxina-Disulfuro/química , Reductasa de Tiorredoxina-Disulfuro/metabolismo
9.
Int J Antimicrob Agents ; 47(3): 195-201, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26895605

RESUMEN

The scourge of multidrug-resistant bacterial infections necessitates the urgent development of novel antimicrobials to address this public health challenge. Drug repurposing is a proven strategy to discover new antimicrobial agents; given that these agents have undergone extensive toxicological and pharmacological analysis, repurposing is an effective method to reduce the time, cost and risk associated with traditional antibiotic innovation. In this study, the in vitro and in vivo antibacterial activities of an antirheumatic drug, auranofin, was investigated against multidrug-resistant Staphylococcus aureus. The results indicated that auranofin possesses potent antibacterial activity against all tested strains of S. aureus, including meticillin-resistant S. aureus (MRSA), vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA), with minimum inhibitory concentrations (MICs) ranging from 0.0625µg/mL to 0.125µg/mL. In vivo, topical auranofin proved superior to conventional antimicrobials, including fusidic acid and mupirocin, in reducing the mean bacterial load in infected wounds in a murine model of MRSA skin infection. In addition to reducing the bacterial load, topical treatment of auranofin greatly reduced the production of inflammatory cytokines, including tumour necrosis factor-α (TNFα), interleukin-6 (IL-6), interleukin-1 beta (IL-1ß) and monocyte chemoattractant protein-1 (MCP-1), in infected skin lesions. Moreover, auranofin significantly disrupted established in vitro biofilms of S. aureus and Staphylococcus epidermidis, more so than the traditional antimicrobials linezolid and vancomycin. Taken together, these results support that auranofin has potential to be repurposed as a topical antimicrobial agent for the treatment of staphylococcal skin and wound infections.


Asunto(s)
Antibacterianos/uso terapéutico , Auranofina/uso terapéutico , Reposicionamiento de Medicamentos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Infecciones Cutáneas Estafilocócicas/tratamiento farmacológico , Staphylococcus epidermidis/efectos de los fármacos , Animales , Biopelículas/efectos de los fármacos , Línea Celular , Quimiocina CCL2/biosíntesis , Farmacorresistencia Bacteriana Múltiple , Quimioterapia Combinada , Femenino , Ácido Fusídico/uso terapéutico , Humanos , Interleucina-1beta/biosíntesis , Interleucina-6/biosíntesis , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Mupirocina/uso terapéutico , Infecciones Cutáneas Estafilocócicas/microbiología , Factor de Necrosis Tumoral alfa/biosíntesis
10.
Exp Parasitol ; 166: 189-93, 2016 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26183422

RESUMEN

Chagas disease, Sleeping Sickness, Nagana and Leishmaniasis are serious infections caused by protozoa of the order Kinetoplastidae. They were described over a century ago by seminal work of different physician-researchers and, despite the initial discoveries, few drugs have been made available for the treatment of these infections. The drugs available present serious efficacy and toxicity problems. Moreover, the emergence of resistant strains has rendered the development of novel chemotherapeutic strategies a priority. Auranofin is currently in use to treat rheumatoid arthritis in humans. Previous reports showed that this compound presents activity against Trypanosoma brucei and Leishmania cells. In Trypanosoma cruzi cells, auranofin resulted in a more potent compound than benznidazole in vitro when tested in different DTUs. In vivo experiments, although not decreasing T. cruzi parasitemia, decreases host mortality. Therefore, we propose auranofin as a potential alternative for a new chemotherapy in Chagas disease with the added advantage of already being approved for use in humans.


Asunto(s)
Auranofina/farmacología , Enfermedad de Chagas/tratamiento farmacológico , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Antirreumáticos/farmacología , Antirreumáticos/uso terapéutico , Auranofina/uso terapéutico , Línea Celular , Enfermedad de Chagas/parasitología , Femenino , Fibroblastos/parasitología , Humanos , Concentración 50 Inhibidora , Dosificación Letal Mediana , Ratones , Ratones Endogámicos BALB C , Nitroimidazoles/farmacología , Parasitemia/tratamiento farmacológico , Parasitemia/parasitología , Distribución Aleatoria , Organismos Libres de Patógenos Específicos , Tripanocidas/uso terapéutico
12.
Redox Biol ; 5: 319-327, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26114584

RESUMEN

Transforming growth factor ß-activated kinase 1 (TAK1) is critical for survival of many KRAS mutated colorectal cancer cells, and TAK1 inhibition with 5Z-7-oxozeaenol has been associated with oxidative stress leading to tumor cell killing. When SW 620 and HCT 116 human colon cancer cells were treated with 5µM 5Z-7-oxozeaenol, cell viability, growth, and clonogenic survival were significantly decreased. Consistent with TAK1 inhibition being causally related to thiol-mediated oxidative stress, 10mM N-acetylcysteine (NAC) partially reversed the growth inhibitory effects of 5Z-7-oxozeaenol. In addition, 5Z-7-oxozeaenol also increased steady-state levels of H2DCFDA oxidation as well as increased levels of total glutathione (GSH) and glutathione disulfide (GSSG). Interestingly, depletion of GSH using buthionine sulfoximine did not significantly potentiate 5Z-7-oxozeaenol toxicity in either cell line. In contrast, pre-treatment of cells with auranofin (Au) to inhibit thioredoxin reductase activity significantly increased levels of oxidized thioredoxin as well as sensitized cells to 5Z-7-oxozeaenol-induced growth inhibition and clonogenic cell killing. These results were confirmed in SW 620 murine xenografts, where treatment with 5Z-7-oxozeaenol or with Au plus 5Z-7-oxozeaenol significantly inhibited growth, with Au plus 5Z-7-oxozeaenol trending toward greater growth inhibition compared to 5Z-7-oxozeaenol alone. These results support the hypothesis that thiol-mediated oxidative stress is causally related to TAK1-induced colon cancer cell killing. In addition, these results support the hypothesis that thioredoxin metabolism is a critical target for enhancing colon cancer cell killing via TAK1 inhibition and could represent an effective therapeutic strategy in patients with these highly resistant tumors.


Asunto(s)
Quinasas Quinasa Quinasa PAM/metabolismo , Tiorredoxinas/metabolismo , Proteínas ras/genética , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Antineoplásicos/toxicidad , Auranofina/química , Auranofina/uso terapéutico , Auranofina/toxicidad , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Femenino , Glutatión/metabolismo , Células HCT116 , Humanos , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Ratones , Ratones Desnudos , Mutación , Estrés Oxidativo/efectos de los fármacos , Reductasa de Tiorredoxina-Disulfuro/antagonistas & inhibidores , Reductasa de Tiorredoxina-Disulfuro/metabolismo , Trasplante Heterólogo , Zearalenona/análogos & derivados , Zearalenona/química , Zearalenona/uso terapéutico , Zearalenona/toxicidad , Proteínas ras/metabolismo
13.
Drugs R D ; 15(1): 13-20, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25698589

RESUMEN

Drug discovery, development and registration is an expensive and time-consuming process associated with a high failure rate [Pessetto et al. (Mol Cancer Ther 12:1299-1309, 2013), Woodcock and Woosley (Annu Rev Med 59:1-12, 2008)]. Drug 'repurposing' is the identification of new therapeutic purposes for already approved drugs and is more affordable and achievable than novel drug discovery [Pessetto et al. (Mol Cancer Ther 12:1299-1309, 2013)]. Auranofin is a drug that is approved for the treatment of rheumatoid arthritis but is being investigated for potential therapeutic application in a number of other diseases including cancer, neurodegenerative disorders, HIV/AIDS, parasitic infections and bacterial infections [Tejman-Yarden et al. (Antimicrob Agents Chemother 57:2029-2035, 2013)]. The main mechanism of action of auranofin is through the inhibition of reduction/oxidation (redox) enzymes that are essential for maintaining intracellular levels of reactive oxygen species. Inhibition of these enzymes leads to cellular oxidative stress and intrinsic apoptosis [Pessetto et al. (Mol Cancer Ther 12:1299-1309, 2013), Fan et al. (Cell Death Dis 5:e1191, 2014), Fiskus et al. (Cancer Res 74:2520-2532, 2014), Marzano et al. (Free Radic Biol Med 42:872-881, 2007)]. Drugs such as auranofin that have already been approved for human use [Tejman-Yarden et al. (Antimicrob Agents Chemother 57:2029-2035, 2013)] can be brought into clinical use for other diseases relatively quickly and for a fraction of the cost of new drugs.


Asunto(s)
Auranofina/uso terapéutico , Reposicionamiento de Medicamentos , Especies Reactivas de Oxígeno/metabolismo , Antirreumáticos/farmacología , Antirreumáticos/uso terapéutico , Apoptosis/efectos de los fármacos , Auranofina/farmacología , Humanos , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos
14.
PLoS Negl Trop Dis ; 9(2): e0003534, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25700363

RESUMEN

Two major human diseases caused by filariid nematodes are onchocerciasis, or river blindness, and lymphatic filariasis, which can lead to elephantiasis. The drugs ivermectin, diethylcarbamazine (DEC), and albendazole are used in control programs for these diseases, but are mainly effective against the microfilarial stage and have minimal or no effect on adult worms. Adult Onchocerca volvulus and Brugia malayi worms (macrofilariae) can live for up to 15 years, reproducing and allowing the infection to persist in a population. Therefore, to support control or elimination of these two diseases, effective macrofilaricidal drugs are necessary, in addition to current drugs. In an effort to identify macrofilaricidal drugs, we screened an FDA-approved library with adult worms of Brugia spp. and Onchocerca ochengi, third-stage larvae (L3s) of Onchocerca volvulus, and the microfilariae of both O. ochengi and Loa loa. We found that auranofin, a gold-containing drug used for rheumatoid arthritis, was effective in vitro in killing both Brugia spp. and O. ochengi adult worms and in inhibiting the molting of L3s of O. volvulus with IC50 values in the low micromolar to nanomolar range. Auranofin had an approximately 43-fold higher IC50 against the microfilariae of L. loa compared with the IC50 for adult female O. ochengi, which may be beneficial if used in areas where Onchocerca and Brugia are co-endemic with L. loa, to prevent severe adverse reactions to the drug-induced death of L. loa microfilariae. Further testing indicated that auranofin is also effective in reducing Brugia adult worm burden in infected gerbils and that auranofin may be targeting the thioredoxin reductase in this nematode.


Asunto(s)
Auranofina/uso terapéutico , Filariasis Linfática/tratamiento farmacológico , Loiasis/tratamiento farmacológico , Microfilarias/efectos de los fármacos , Oncocercosis/tratamiento farmacológico , Adulto , Albendazol/uso terapéutico , Animales , Antihelmínticos/uso terapéutico , Brugia Malayi/efectos de los fármacos , Bovinos , Línea Celular , Dietilcarbamazina/uso terapéutico , Reposicionamiento de Medicamentos , Filariasis Linfática/parasitología , Femenino , Filaricidas/uso terapéutico , Gerbillinae , Haplorrinos , Humanos , Ivermectina/uso terapéutico , Loa/efectos de los fármacos , Loiasis/parasitología , Onchocerca volvulus/efectos de los fármacos , Oncocercosis/parasitología
15.
Oncology ; 88(4): 208-13, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25502607

RESUMEN

PURPOSE: This trial was undertaken (1) to determine the feasibility of enrolling asymptomatic ovarian cancer patients with CA-125 elevation in a trial with the protein kinase C iota (PKCι) inhibitor auranofin and (2) to understand patients' perceptions of CA-125 monitoring. METHODS: Asymptomatic ovarian cancer patients with CA-125 elevation received 3 mg auranofin orally twice per day and were evaluated. The patients participated in interviews about CA-125 monitoring. RESULTS: Ten patients were enrolled in slightly over 6 months, exceeding our anticipated accrual rate. Four manifested stable CA-125 levels for 1 month or longer. The median progression-free survival was 2.8 months (95% CI: 1.3-3.8); auranofin was well tolerated. One patient had baseline and monthly CA-125 levels of 5,570, 6,085, 3,511, and 2,230 U/ml, respectively, stopped auranofin because of radiographic progression at 3 months, and manifested an increase in CA-125 to 7,168 U/ml approximately 3 months later. Patient interviews revealed (1) the important role of CA-125 in cancer monitoring, (2) ardent advocacy of CA-125 testing, and (3) an evolution toward CA-125 assuming a life of its own. CONCLUSIONS: This study showed the feasibility of enrolling asymptomatic ovarian cancer patients with CA-125 elevation in a trial with auranofin. One patient had a decline in CA-125, suggesting that PKCι inhibition merits further study in ovarian cancer.


Asunto(s)
Antirreumáticos/uso terapéutico , Auranofina/uso terapéutico , Isoenzimas/antagonistas & inhibidores , Neoplasias Ováricas/tratamiento farmacológico , Proteína Quinasa C/antagonistas & inhibidores , Administración Oral , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Antígeno Ca-125/metabolismo , Esquema de Medicación , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/enzimología , Neoplasias Ováricas/patología , Proyectos Piloto , Pronóstico , Tasa de Supervivencia
16.
PLoS Negl Trop Dis ; 8(7): e2973, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25079790

RESUMEN

BACKGROUND: The mainstay of toxoplasmosis treatment targets the folate biosynthetic pathways and has not changed for the last 50 years. The activity of these chemotherapeutic agents is restricted to one lifecycle stage of Toxoplasma gondii, they have significant toxicity, and the impending threat of emerging resistance to these agents makes the discovery of new therapies a priority. We now demonstrate that auranofin, an orally administered gold containing compound that was FDA approved for treatment of rheumatoid arthritis, has activity against Toxoplasma gondii in vitro (IC50 = 0.28 µM) and in vivo (1 mg/kg). METHODS/PRINCIPAL FINDINGS: Replication within human foreskin fibroblasts of RH tachyzoites was inhibited by auranofin. At 0.4 µM, auranofin inhibited replication, as measured by percent infected fibroblasts at 24 hrs, (10.94% vs. 24.66% of controls; p = 0.0003) with no effect on parasite invasion (16.95% vs. 12.91% p = 0.4331). After 18 hrs, 62% of extracellular parasites treated with auranofin were non-viable compared to control using an ATP viability assay (p = 0.0003). In vivo, a previously standardized chicken embryo model of acute toxoplasmosis was used. Fourteen day old chicken embryos were injected through the chorioallantoic vein with 1×104 tachyzoites of the virulent RH strain. The treatment group received one dose of auranofin at the time of inoculation (1 mg/kg estimated body weight). On day 5, auranofin-treated chicken embryos were 100% protected against death (p = 0.0002) and had a significantly reduced parasite load as determined by histopathology, immunohistochemistry and by the number of parasites quantified by real-time PCR. CONCLUSIONS: These results reveal in vitro and in vivo activity of auranofin against T. gondii, suggesting that it may be an effective alternative treatment for toxoplasmosis.


Asunto(s)
Antiprotozoarios/uso terapéutico , Auranofina/uso terapéutico , Toxoplasma/efectos de los fármacos , Toxoplasmosis/tratamiento farmacológico , Animales , Antiprotozoarios/farmacología , Auranofina/farmacología , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Embrión de Pollo , Modelos Animales de Enfermedad , Reposicionamiento de Medicamentos , Fibroblastos/parasitología , Histocitoquímica , Humanos , Inmunohistoquímica , Concentración 50 Inhibidora , Carga de Parásitos , Pruebas de Sensibilidad Parasitaria , Reacción en Cadena en Tiempo Real de la Polimerasa , Toxoplasma/crecimiento & desarrollo , Toxoplasma/fisiología , Resultado del Tratamiento
17.
Biometals ; 27(4): 787-91, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24820140

RESUMEN

Auranofin, (AF), a gold(I) complex in clinical use for the therapy of rheumatoid arthritis, is reported here to produce remarkable bactericidal effects in vitro against Staphylococcus sp. Noticeably, a similar antimicrobial action and potency are also noticed toward a few methicillin-resistant Staphylococcus aureus strains but not toward Escherichia coli. The time and concentration dependencies of the antimicrobial actions of AF have been characterized through recording time kill curves, and a concentration dependent profile highlighted. Overall, the present results point out that auranofin might be quickly and successfully repurposed for the treatment of severe bacterial infections due to resistant Staphylococci.


Asunto(s)
Antibacterianos/farmacología , Auranofina/farmacología , Infecciones Estafilocócicas/tratamiento farmacológico , Antibacterianos/uso terapéutico , Auranofina/uso terapéutico , Reposicionamiento de Medicamentos , Humanos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana
18.
ACS Chem Biol ; 9(3): 663-72, 2014 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-24328400

RESUMEN

Cutaneous leishmaniasis remains ignored in therapeutic drug discovery programs worldwide. This is mainly because cutaneous leishmaniasis is frequently a disease of impoverished populations in countries where funds are limited for research and patient care. However, the health burden of individuals in endemic areas mandates readily available, effective, and safe treatments. Of the existing cutaneous leishmaniasis therapeutics, many are growth inhibitory to Leishmania parasites, potentially creating dormant parasite reservoirs that can be activated when host immunity is compromised, enabling the reemergence of cutaneous leishmaniasis lesions or worse spread of Leishmania parasites to other body sites. To accelerate the identification and development of novel cutaneous leishmaniasis therapeutics, we designed an integrated in vitro and in vivo screening platform that incorporated multiple Leishmania life cycles and species and probed a focused library of pharmaceutically active compounds. The objective of this phenotypic drug discovery platform was the identification and prioritization of bona fide cytotoxic chemotypes toward Leishmania parasites. We identified the Food and Drug Administration-approved drug auranofin, a known inhibitor of Leishmania promastigote growth, as a potent cytotoxic anti-leishmanial agent and inducer of apoptotic-like death in promastigotes. Significantly, the anti-leishmanial activity of auranofin transferred to cell-based amastigote assays as well as in vivo murine models. With appropriate future investigation, these data may provide the foundation for potential exploitation of gold(I)-based complexes as chemical tools or the basis of therapeutics for leishmaniasis. Thus, auranofin may represent a prototype drug that can be used to identify signaling pathways within the parasite and host cell critical for parasite growth and survival.


Asunto(s)
Antiprotozoarios/farmacología , Apoptosis/efectos de los fármacos , Auranofina/farmacología , Leishmania/efectos de los fármacos , Leishmaniasis/tratamiento farmacológico , Animales , Antiprotozoarios/química , Antiprotozoarios/uso terapéutico , Auranofina/química , Auranofina/uso terapéutico , Descubrimiento de Drogas , Ensayos Analíticos de Alto Rendimiento , Leishmania/patogenicidad , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Relación Estructura-Actividad
19.
Comput Methods Programs Biomed ; 113(2): 557-68, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24286728

RESUMEN

This article describes a new software for modeling correlated binary data based on orthogonalized residuals, a recently developed estimating equations approach that includes, as a special case, alternating logistic regressions. The software is flexible with respect to fitting in that the user can choose estimating equations for association models based on alternating logistic regressions or orthogonalized residuals, the latter choice providing a non-diagonal working covariance matrix for second moment parameters providing potentially greater efficiency. Regression diagnostics based on this method are also implemented in the software. The mathematical background is briefly reviewed and the software is applied to medical data sets.


Asunto(s)
Modelos Logísticos , Programas Informáticos , Artritis/tratamiento farmacológico , Auranofina/uso terapéutico , Ensayos Clínicos como Asunto , Análisis por Conglomerados , Femenino , Humanos , Masculino
20.
Biometrics ; 69(3): 633-40, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23724948

RESUMEN

In this article, we propose a generalized estimating equations (GEE) approach for correlated ordinal or nominal multinomial responses using a local odds ratios parameterization. Our motivation lies upon observing that: (i) modeling the dependence between correlated multinomial responses via the local odds ratios is meaningful both for ordinal and nominal response scales and (ii) ordinary GEE methods might not ensure the joint existence of the estimates of the marginal regression parameters and of the dependence structure. To avoid (ii), we treat the so-called "working" association vector α as a "nuisance" parameter vector that defines the local odds ratios structure at the marginalized contingency tables after tabulating the responses without a covariate adjustment at each time pair. To estimate α and simultaneously approximate adequately possible underlying dependence structures, we employ the family of association models proposed by Goodman. In simulations, the parameter estimators with the proposed GEE method for a marginal cumulative probit model appear to be less biased and more efficient than those with the independence "working" model, especially for studies having time-varying covariates and strong correlation.


Asunto(s)
Biometría/métodos , Oportunidad Relativa , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/fisiopatología , Auranofina/uso terapéutico , Fenómenos Biomecánicos , Simulación por Computador , Humanos , Estudios Longitudinales , Modelos Estadísticos , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Programas Informáticos
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