Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.269
Filtrar
1.
Microbiol Spectr ; 12(2): e0296823, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38206030

RESUMO

Auranofin, an FDA-approved drug for rheumatoid arthritis, has emerged as a promising antiparasitic medication in recent years. The gold(I) ion in auranofin is postulated to be responsible for its antiparasitic activity. Notably, aurothiomalate and aurothioglucose also contain gold(I), and, like auranofin, they were previously used to treat rheumatoid arthritis. Whether they have antiparasitic activity remains to be elucidated. Herein, we demonstrated that auranofin and similar derivatives, but not aurothiomalate and aurothioglucose, inhibited the growth of Toxoplasma gondii in vitro. We found that auranofin affected the T. gondii biological cycle (lytic cycle) by inhibiting T. gondii's invasion and triggering its egress from the host cell. However, auranofin could not prevent parasite replication once T. gondii resided within the host. Auranofin treatment induced apoptosis in T. gondii parasites, as demonstrated by its reduced size and elevated phosphatidylserine externalization (PS). Notably, the gold from auranofin enters the cytoplasm of T. gondii, as demonstrated by scanning transmission electron microscopy-energy dispersive X-ray spectroscopy (STEM-EDS) and Inductively Coupled Plasma-Mass Spectrometry (ICP-MS).IMPORTANCEToxoplasmosis, caused by Toxoplasma gondii, is a devastating disease affecting the brain and the eyes, frequently affecting immunocompromised individuals. Approximately 60 million people in the United States are already infected with T. gondii, representing a population at-risk of developing toxoplasmosis. Recent advances in treating cancer, autoimmune diseases, and organ transplants have contributed to this at-risk population's exponential growth. Paradoxically, treatments for toxoplasmosis have remained the same for more than 60 years, relying on medications well-known for their bone marrow toxicity and allergic reactions. Discovering new therapies is a priority, and repurposing FDA-approved drugs is an alternative approach to speed up drug discovery. Herein, we report the effect of auranofin, an FDA-approved drug, on the biological cycle of T. gondii and how both the phosphine ligand and the gold molecule determine the anti-parasitic activity of auranofin and other gold compounds. Our studies would contribute to the pipeline of candidate anti-T. gondii agents.


Assuntos
Artrite Reumatoide , Fosfinas , Toxoplasma , Toxoplasmose , Humanos , Auranofina/farmacologia , Auranofina/uso terapêutico , Ouro/farmacologia , Ouro/uso terapêutico , Ligantes , Aurotioglucose/farmacologia , Aurotioglucose/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Tiomalato Sódico de Ouro/farmacologia , Tiomalato Sódico de Ouro/uso terapêutico , Antiparasitários/farmacologia , Antiparasitários/uso terapêutico
2.
Chem Rev ; 123(10): 6612-6667, 2023 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-37071737

RESUMO

The gold drugs, gold sodium thiomalate (Myocrisin), aurothioglucose (Solganal), and the orally administered auranofin (Ridaura), are utilized in modern medicine for the treatment of inflammatory arthritis including rheumatoid and juvenile arthritis; however, new gold agents have been slow to enter the clinic. Repurposing of auranofin in different disease indications such as cancer, parasitic, and microbial infections in the clinic has provided impetus for the development of new gold complexes for biomedical applications based on unique mechanistic insights differentiated from auranofin. Various chemical methods for the preparation of physiologically stable gold complexes and associated mechanisms have been explored in biomedicine such as therapeutics or chemical probes. In this Review, we discuss the chemistry of next generation gold drugs, which encompasses oxidation states, geometry, ligands, coordination, and organometallic compounds for infectious diseases, cancer, inflammation, and as tools for chemical biology via gold-protein interactions. We will focus on the development of gold agents in biomedicine within the past decade. The Review provides readers with an accessible overview of the utility, development, and mechanism of action of gold-based small molecules to establish context and basis for the thriving resurgence of gold in medicine.


Assuntos
Artrite Reumatoide , Auranofina , Humanos , Auranofina/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Ouro , Aurotioglucose/farmacologia , Aurotioglucose/uso terapêutico , Tiomalato Sódico de Ouro/farmacologia , Tiomalato Sódico de Ouro/uso terapêutico
3.
Histochem Cell Biol ; 159(3): 225-232, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36864314

RESUMO

The newest data on metallic gold have placed the noble metal central in the fight for the safe treatment of autoimmune inflammation. There are two different ways to use gold for the treatment of inflammation: gold microparticles > 20 µm and gold nanoparticles. The injection of gold microparticles (µGold) is a purely local therapy. µGold particles stay put where injected, and gold ions released from them are relatively few and taken up by cells within a sphere of only a few millimeters in diameter from their origin particles. The macrophage-induced release of gold ions may continue for years. Injection of gold nanoparticles (nanoGold), on the other hand, is spread throughout the whole body, and the bio-released gold ions, therefore, affect multitudes of cells all over the body, as when using gold-containing drugs such as Myocrisin. Since macrophages and other phagocytotic cells take up and transport nanoGold and remove it after a short period, repeated treatment is necessary. This review describes the details of the cellular mechanisms that lead to the bio-release of gold ions in µGold and nanoGold.


Assuntos
Ouro , Nanopartículas Metálicas , Humanos , Inflamação/tratamento farmacológico , Tiomalato Sódico de Ouro , Íons
4.
Acta Parasitol ; 67(2): 640-647, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35380401

RESUMO

PURPOSE: Leishmaniasis is a major public health problem worldwide in many parts of the world. Current anti-leishmanial drugs have only limited clinical efficacy. Aurothiomalate derivatives are useful for treating rheumatoid arthritis, but have emerged as a promising therapeutic candidate for leishmaniasis. This paper gives a review of the literature about the usefulness of aurothiomalate derivatives against leishmaniasis. METHODS: In this study, we reviewed the proposed mechanisms of action of aurothiomalate and related compounds on the metabolism of L. major and collected data by searching relevant articles. RESULTS: Aurothiomalate-based drugs could be effective against leishmaniasis through two direct and indirect mechanisms: first, cytotoxic effects on parasites via thiomalate's false substrate role in the citric acid cycle against malate; and second, immunosuppressive and anti-inflammatory effects of aurothiomalate derivatives with prostaglandin production inhibitory effects. CONCLUSIONS: The current study documented that aurothiomalate-based drugs could be effective against leishmaniasis through two direct and indirect mechanisms of action. Gold thiomalate as a promising hit should be evaluated against L. major in vitro and in vivo conditions in the future.


Assuntos
Leishmania major , Leishmaniose , Tiomalato Sódico de Ouro/metabolismo , Tiomalato Sódico de Ouro/farmacologia , Tiomalato Sódico de Ouro/uso terapêutico , Humanos , Leishmaniose/tratamento farmacológico
5.
Int J Mol Sci ; 22(17)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34502400

RESUMO

Giardiasis represents a latent problem in public health due to the exceptionally pathogenic strategies of the parasite Giardia lamblia for evading the human immune system. Strains resistant to first-line drugs are also a challenge. Therefore, new antigiardial therapies are urgently needed. Here, we tested giardial arginine deiminase (GlADI) as a target against giardiasis. GlADI belongs to an essential pathway in Giardia for the synthesis of ATP, which is absent in humans. In silico docking with six thiol-reactive compounds was performed; four of which are approved drugs for humans. Recombinant GlADI was used in enzyme inhibition assays, and computational in silico predictions and spectroscopic studies were applied to follow the enzyme's structural disturbance and identify possible effective drugs. Inhibition by modification of cysteines was corroborated using Ellman's method. The efficacy of these drugs on parasite viability was assayed on Giardia trophozoites, along with the inhibition of the endogenous GlADI. The most potent drug against GlADI was assayed on Giardia encystment. The tested drugs inhibited the recombinant GlADI by modifying its cysteines and, potentially, by altering its 3D structure. Only rabeprazole and omeprazole decreased trophozoite survival by inhibiting endogenous GlADI, while rabeprazole also decreased the Giardia encystment rate. These findings demonstrate the potential of GlADI as a target against giardiasis.


Assuntos
Giardia lamblia/efeitos dos fármacos , Giardíase/tratamento farmacológico , Hidrolases/metabolismo , Animais , Antiprotozoários/farmacologia , Simulação por Computador , Cisteína/química , Avaliação Pré-Clínica de Medicamentos/métodos , Reposicionamento de Medicamentos/métodos , Giardia lamblia/patogenicidade , Giardíase/imunologia , Tiomalato Sódico de Ouro/farmacologia , Humanos , Hidrolases/efeitos dos fármacos , Hidrolases/ultraestrutura , Omeprazol/farmacologia , Inibidores da Bomba de Prótons/farmacologia , Rabeprazol , Tiamina/análogos & derivados , Tiamina/farmacologia , Trofozoítos/efeitos dos fármacos
6.
Bioorg Chem ; 110: 104749, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33652341

RESUMO

Real-time monitoring of drug metabolism in vivo is of great significance to drug development and toxicology research. The purpose of this study is to establish a rapid and visual in vivo detection method for the detection of an intermediate metabolite of the gold (I) drug. Gold (I) drugs such as sodium aurothiomalate (AuTM) have anti-inflammatory effects in the treatment of rheumatoid arthritis. Gold(III) ions (Au3+) are the intermediate metabolite of gold medicine, and they are also the leading factor of side effects in the treatment of patients. However, the rapid reduction of Au3+ to Au+ by thiol proteins in organisms limits the in-depth study of metabolism of gold drugs in vivo. Here we describe a luminescence Au3+ probe (RA) based on ruthenium (II) complex for detecting Au3+ in vitro and in vivo. RA with large Stokes shift, good water solubility and biocompatibility was successfully applied to detect Au3+ in living cells and vivo by luminescence imaging, and to trap the fluctuation of Au3+ level produced by gold (I) medicine. More importantly, the luminescent probe was used to the detection of the intermediate metabolites of gold (I) drugs for the first time. Overall, this work offers a new detection tool/method for a deeper study of gold (I) drugs metabolite.


Assuntos
Corantes Fluorescentes/química , Tiomalato Sódico de Ouro/química , Tiomalato Sódico de Ouro/metabolismo , Ouro/química , Compostos de Rutênio/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Lipopolissacarídeos/toxicidade , Camundongos , Estrutura Molecular , Células RAW 264.7 , Análise de Célula Única , Peixe-Zebra
8.
Toxicol Appl Pharmacol ; 412: 115379, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33358697

RESUMO

Exposure to heavy metals may have toxic effects on several human organs causing morbidity and mortality. Metals may trigger or exacerbate autoimmunity in humans. Inbred mouse strains with certain H-2 haplotypes are susceptible to xenobiotic-induced autoimmunity; and their immune response to metals such as mercury, gold, and silver have been explored. Serum antinuclear antibodies (ANA), polyclonal B-cell activation, hypergammaglobulinemia and tissue immune complex deposition are the main features of metal-induced autoimmunity in inbred mice. However, inbred mouse strains do not represent the genetic heterogeneity in humans. In this study, outbred Swiss Webster (SW) mice exposed to gold or mercury salts showed immune and autoimmune responses. Intramuscular injection of 22.5 mg/kg.bw aurothiomalate (AuTM) induced IgG ANA in SW mice starting after 5 weeks that persisted until week 15 although with a lower intensity. This was accompanied by elevated serum levels of total IgG antibodies against chromatin and total histones. Exposure to gold led to development of serum IgG autoantibodies corresponding to H1 and H2A histones, and dsDNA. Both gold and mercury induced polyclonal B-cell activation. Eight mg/L mercuric chloride (HgCl2) in drinking water, caused IgG antinucleolar antibodies (ANoA) after 5 weeks in SW mice accompanied by immune complex deposition in kidneys and spleen. Serum IgG antibodies corresponding to anti-fibrillarin, and anti-PM/Scl-100 antibodies, were observed in mercury-exposed SW mice. Gold and mercury trigger systemic autoimmune response in genetically heterogeneous outbred SW mice and suggest them as an appropriate model to study xenobiotic-induced autoimmunity.


Assuntos
Anticorpos Antinucleares/sangue , Autoimunidade/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Tiomalato Sódico de Ouro/toxicidade , Imunoglobulina G/sangue , Ativação Linfocitária/efeitos dos fármacos , Cloreto de Mercúrio/toxicidade , Administração Oral , Animais , Complexo Antígeno-Anticorpo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Cromatina/imunologia , Proteínas Cromossômicas não Histona/imunologia , Exorribonucleases/imunologia , Complexo Multienzimático de Ribonucleases do Exossomo/imunologia , Feminino , Tiomalato Sódico de Ouro/administração & dosagem , Histonas/imunologia , Injeções Intramusculares , Rim/efeitos dos fármacos , Rim/imunologia , Cloreto de Mercúrio/administração & dosagem , Camundongos , Baço/efeitos dos fármacos , Baço/imunologia
9.
Bull Exp Biol Med ; 169(6): 759-764, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33098513

RESUMO

The role of NF-κВ in the realization of the growth potential of neural progenitor cells from the subventricular area of cerebral hemispheres and secretion of neurotrophins by glial elements was studied under conditions of in vitro and in vivo modeled ethanol-induced neurodegeneration. It was found that this transcription factor does not participate in the regulation of mitotic activity of neural stem cells and neuronal-committed progenitors under optimal conditions and under the influence of ethanol in vitro. At the same time, NF-κВ suppresses differentiation/maturation of neural progenitor cells. Long-term peroral administration of ethanol to mice was accompanied by the inhibitory influence of NF-κВ on proliferation of progenitor cells. Blockade of NF-κВ in neural stem cells and committed neuronal precursors in animals with neurodegeneration induced cell cycle progression in these elements. The involvement of NF-κВ in the secretory function of astrocytes and oligodendrogliocytes was established. Inactivation of the nuclear transcription factor reduced the production of neurotrophins, in particular, in the case of ethanol exposure. At the same time, no changes in the function of microglia were noted.


Assuntos
Ventrículos Laterais/efeitos dos fármacos , NF-kappa B/genética , Células-Tronco Neurais/efeitos dos fármacos , Doenças Neurodegenerativas/genética , Regeneração/efeitos dos fármacos , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Etanol/farmacologia , Regulação da Expressão Gênica , Tiomalato Sódico de Ouro/farmacologia , Ventrículos Laterais/metabolismo , Ventrículos Laterais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , NF-kappa B/metabolismo , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/metabolismo , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Cultura Primária de Células , Regeneração/genética , Transdução de Sinais
10.
Bull Exp Biol Med ; 169(4): 426-430, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32889566

RESUMO

Suppression of the production of granulocytic CSF under the effect of 5-fluorouracyl is related to disorders in the NF-κB-, cAMP-dependent signaling pathways and MAPK cascade. These secondary messengers are involved in the regulation of functional activity of nonadherent myelokaryocytes starting from day 10 of the experiment (initial period of the hemopoietic granulocytic stem regeneration after antimetabolite challenge). Granulocytic CSF does not play essential role in the formation of colony-stimulating activity of cells of the adherent and nonadherent fractions of the bone marrow. Only cAMP-dependent pathway is involved in the regulation of the realization of the granulocytic precursor growth potential in response to the challenge.


Assuntos
Citostáticos/farmacologia , Fluoruracila/farmacologia , Fator Estimulador de Colônias de Granulócitos/genética , Granulócitos/efeitos dos fármacos , Hematopoese/efeitos dos fármacos , NF-kappa B/genética , Adenilil Ciclases/genética , Adenilil Ciclases/metabolismo , Animais , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Adesão Celular/efeitos dos fármacos , AMP Cíclico/metabolismo , Didesoxiadenosina/análogos & derivados , Didesoxiadenosina/farmacologia , Regulação da Expressão Gênica , Tiomalato Sódico de Ouro/farmacologia , Fator Estimulador de Colônias de Granulócitos/metabolismo , Granulócitos/citologia , Granulócitos/metabolismo , Hematopoese/genética , Imidazóis/farmacologia , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Piridinas/farmacologia , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
11.
Biometals ; 32(5): 813-817, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31473877

RESUMO

The study of metal-based drugs represents an important branch of modern bioinorganic chemistry. The growing importance of this field is linked to the large success in medicine of a few metal based drugs, either in clinical use or still experimental. Moreover, these metal-based drugs are frequently used as reference compounds to assess comparatively the behavior of newly synthesized metallodrugs. For the convenience of researchers working in this area we report here a compilation of the relevant analytical and spectroscopic data of ten representative metallodrugs based on Platinum, Ruthenium, Gold and Mercury. The selected compounds, namely Cisplatin, Oxaliplatin, Carboplatin, Auranofin, Sodium Aurothiomalate, NAMI-A, KP1019, Thimerosal, Merbromin and Phenylmercury Acetate, were chosen owing to their importance in the field. We believe that this compilation may turn very helpful to researchers as these data are difficult to find and generally scattered over a large number of (old) publications.


Assuntos
Complexos de Coordenação/química , Auranofina/química , Carboplatina/química , Cisplatino/química , Ouro/química , Tiomalato Sódico de Ouro/química , Merbromina/química , Mercúrio/química , Oxaliplatina/química , Compostos de Fenilmercúrio/química , Platina/química , Rutênio/química
12.
Bull Exp Biol Med ; 166(3): 344-347, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30627910

RESUMO

The role of signaling molecules in synthesis of humoral regulators of granulocytopoiesis by the hematopoietic microenvironmental cells during stress was analyzed using specific inhibitors. The major role in stimulation of the synthesis of granulocytic CSF during stressful stimulation is played by PI3K/Akt signaling cascade. Nuclear transcription factor NF-κB plays an auxiliary role in the regulation of functional activity of the bone marrow mononuclears. However, this factor affects the synthesis of granulocytic CSF by CD4+ cells of the bone marrow in response to stressful stimulation. Different degree and specific character of involvement of the signaling proteins in the regulation of the production of humoral factors determining colony-stimulating activity are explained by changes in functional state of monocyte-derived macrophages in different periods of stress response.


Assuntos
Fator Estimulador de Colônias de Granulócitos/genética , Granulócitos/imunologia , NF-kappa B/genética , Fosfatidilinositol 3-Quinases/genética , Transdução de Sinais/imunologia , Estresse Psicológico/genética , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Células da Medula Óssea/patologia , Cromonas/farmacologia , Flavonoides/farmacologia , Regulação da Expressão Gênica , Tiomalato Sódico de Ouro/farmacologia , Fator Estimulador de Colônias de Granulócitos/imunologia , Granulócitos/efeitos dos fármacos , Granulócitos/patologia , Imidazóis/farmacologia , Imobilização/métodos , Leucopoese/efeitos dos fármacos , Leucopoese/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/imunologia , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/imunologia , Morfolinas/farmacologia , NF-kappa B/antagonistas & inibidores , NF-kappa B/imunologia , Fosfatidilinositol 3-Quinases/imunologia , Inibidores de Fosfoinositídeo-3 Quinase , Piridinas/farmacologia , Estresse Psicológico/imunologia , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
13.
Enzyme Microb Technol ; 116: 6-15, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29887018

RESUMO

Cells of Escherichia coli Rosetta, containing plasmid pET-28a with sequences of DNA of chitinase from Stenotrophomonas maltophilia N4, were used for the efficient synthesis of recombinant chitinolytic enzyme. The objective of this study was to improve thermal stability of the recombinant chitinase by salts and metal nanoparticles (NP). The studied chitinase was thermolabile and largely lost its activity in the first minutes of storage at 50 and 60 °C. The optimum temperature for colloidal chitin hydrolysis by the enzyme was 50 °C. Application of sodium aurothiomalate hydrate and manganese chloride enhanced the activity of the recombinant enzyme. In general, chitinase activity was higher when silver nanoparticles (Ag-NP) were used, but lower for other NP. The thermal stability of chitinase immobilized on Ag-NP and manganese chloride was significantly higher than that of free chitinase. Chitinase thermal stability after gold and manganese oxide nanoparticle application was higher than that of the control at 50 °C. Platinum nanoparticles had no significant effect on thermostability. The Ag-NP had a smaller diameter (from 2 to 20 nm) than Au-NP (from 5 to 70 nm) and Pt-NP (from 4 to 80 nm). The TEM analysis showed that the used NP had a higher affinity for chitinase than for the synthetic substrate. The type, size, and location of the NP on the enzyme played a major role in the thermal stability of chitinase.


Assuntos
Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Quitinases/química , Quitinases/metabolismo , Stenotrophomonas maltophilia/enzimologia , Proteínas de Bactérias/genética , Quitinases/genética , Cloretos/química , Cloretos/metabolismo , Estabilidade Enzimática , Escherichia coli/genética , Escherichia coli/metabolismo , Tiomalato Sódico de Ouro/química , Tiomalato Sódico de Ouro/metabolismo , Hidrólise , Compostos de Manganês/química , Compostos de Manganês/metabolismo , Nanopartículas Metálicas/química , Óxidos , Stenotrophomonas maltophilia/química , Stenotrophomonas maltophilia/genética , Temperatura
15.
Small GTPases ; 8(1): 58-64, 2017 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-27245608

RESUMO

Lung cancer is the leading cause of cancer death in the US with ∼124,000 new cases annually, and a 5 y survival rate of ∼16%. Mutant KRAS-driven lung adenocarcinoma (KRAS LADC) is a particularly prevalent and deadly form of lung cancer. Protein kinase Cι (PKCι) is an oncogenic effector of KRAS that activates multiple signaling pathways that stimulate transformed growth and invasion, and maintain a KRAS LADC tumor-initiating cell (TIC) phenotype. PKCι inhibitors used alone and in strategic combination show promise as new therapeutic approaches to treatment of KRAS LADC. These novel drug combinations may improve clinical management of KRAS LADC.


Assuntos
Tiomalato Sódico de Ouro/administração & dosagem , Isoenzimas/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Proteína Quinase C/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Sirolimo/administração & dosagem , Células A549 , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Tiomalato Sódico de Ouro/farmacologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Mutação , Células-Tronco Neoplásicas/efeitos dos fármacos , Sirolimo/farmacologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Oncotarget ; 6(17): 15297-310, 2015 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-25915428

RESUMO

Pancreatic cancer is highly resistant to current chemotherapies. Identification of the critical signaling pathways that mediate pancreatic cancer transformed growth is necessary for the development of more effective therapeutic treatments. Recently, we demonstrated that protein kinase C iota (PKCι) and zeta (PKCζ) promote pancreatic cancer transformed growth and invasion, by activating Rac1→ERK and STAT3 signaling pathways, respectively. However, a key question is whether PKCι and PKCζ play redundant (or non-redundant) roles in pancreatic cancer cell transformed growth. Here we describe the novel observations that 1) PKCι and PKCζ are non-redundant in the context of the transformed growth of pancreatic cancer cells; 2) a gold-containing small molecule known to disrupt the PKCι/Par6 interaction, aurothiomalate, also disrupts PKCζ/Par6 interaction; 3) aurothiomalate inhibits downstream signaling of both PKCι and PKCζ, and blocks transformed growth of pancreatic cancer cells in vitro; and 4) aurothiomalate inhibits pancreatic cancer tumor growth and metastasis in vivo. Taken together, these data provide convincing evidence that an inhibitor of atypical PKC signaling inhibits two key oncogenic signaling pathways, driven non-redundantly by PKCι and PKCζ, to significantly reduce tumor growth and metastasis. Our results demonstrate that inhibition of atypical PKC signaling is a promising therapeutic strategy to treat pancreatic cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Tiomalato Sódico de Ouro/farmacologia , Isoenzimas/antagonistas & inibidores , Neoplasias Pancreáticas/patologia , Proteína Quinase C/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/patologia , Humanos , Isoenzimas/genética , Invasividade Neoplásica/patologia , Ligação Proteica , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Interferência de RNA , RNA Interferente Pequeno , Transdução de Sinais/efeitos dos fármacos
18.
J Inorg Biochem ; 149: 102-7, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25865000

RESUMO

Aurothiomalate (AuTm) is an old, clinically established, antiarthritic gold drug that is currently being reconsidered as a candidate drug for cancer treatment and for other therapeutic indications within a more general drug repositioning program. As the biological effects of gold drugs seem to be mediated, mainly, by their interactions with protein targets we have analyzed here, in detail, the metalation patterns produced by aurothiomalate in a few model proteins. In particular, the reactions of aurothiomalate with the small proteins ribonuclease A, cytochrome c and lysozyme were explored through ESI MS (electrospray ionization mass spectrometry) analysis. Notably, characteristic and rather constant features emerged in the protein metalation patterns induced by AuTm that are markedly distinct from those caused by auranofin; a non-covalent interaction mode is invoked for AuTm binding to the mentioned proteins. The affinity constants of AuTm toward the three mentioned proteins were also initially assessed. The implications of the present findings are discussed.


Assuntos
Antineoplásicos/farmacologia , Auranofina/farmacologia , Citocromos c/metabolismo , Tiomalato Sódico de Ouro/farmacologia , Muramidase/metabolismo , Ribonuclease Pancreático/metabolismo , Sequência de Aminoácidos , Antineoplásicos/química , Auranofina/química , Sítios de Ligação , Citocromos c/química , Tiomalato Sódico de Ouro/química , Dados de Sequência Molecular , Muramidase/química , Ligação Proteica , Ribonuclease Pancreático/química
19.
Bull Exp Biol Med ; 158(5): 624-7, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25778647

RESUMO

We studied the role of NF-κB/IKK-mediated signaling in the stimulation of growth potential of mesenchymal progenitor cells by alkaloid songorine in vitro. Specific NF-κB inhibitor oridonin abolished activation of proliferation and differentiation of progenitor cells. Aurothiomalate, a selective blocker of IKK-2, also suppressed mitotic activity of fibroblast precursors, but had no effect on the rate of the differentiation.


Assuntos
Alcaloides/farmacologia , Quinase I-kappa B/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , NF-kappa B/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Diterpenos do Tipo Caurano/farmacologia , Tiomalato Sódico de Ouro/farmacologia , Quinase I-kappa B/antagonistas & inibidores , Camundongos , Modelos Biológicos , NF-kappa B/antagonistas & inibidores , Medicina Regenerativa
20.
Scand J Rheumatol ; 44(1): 74-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25314295

RESUMO

OBJECTIVES: Microsomal prostaglandin E synthase-1 (mPGES-1) is a terminal enzyme in the production of prostaglandin E2 (PGE2) and its expression is upregulated during inflammation. mPGES-1 is considered as a potential drug target for the treatment of arthritis to reduce adverse effects related to the current non-steroidal anti-inflammatory drugs (NSAIDs). Our aim was to study the expression of mPGES-1 in primary human chondrocytes and whether the expression is affected by clinically used antirheumatic drugs. METHOD: Primary human chondrocytes were isolated from cartilage samples obtained from patients undergoing total knee replacement surgery. Expression of mPGES-1 was studied by quantitative real-time polymerase chain reaction (PCR) and Western blot analysis. PGE2 levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: mPGES-1 expression in primary human chondrocytes was enhanced when the cells were exposed to interleukin-1ß (IL-1ß) and mPGES-1 protein levels continued to increase up to the 96-h follow-up. Aurothiomalate inhibited mPGES-1 expression and PGE2 production in a dose-dependent manner, as did the anti-inflammatory steroid dexamethasone. Other disease-modifying antirheumatic drugs (DMARDs) studied (sulfasalazine, methotrexate, and hydroxychloroquine) did not alter mPGES-1 expression. CONCLUSIONS: The results introduce aurothiomalate as the first, and so far the only, DMARD found to be able to inhibit mPGES-1 expression. The effect is likely involved in the mechanisms of action of this gold-containing DMARD in rheumatic diseases. The results are implicated in the regulatory mechanisms of mPGES-1 expression, which are under intensive research.


Assuntos
Antirreumáticos/farmacologia , Condrócitos/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Tiomalato Sódico de Ouro/farmacologia , Oxirredutases Intramoleculares/genética , Condrócitos/citologia , Condrócitos/fisiologia , Dexametasona/farmacologia , Dinoprostona/biossíntese , Ensaio de Imunoadsorção Enzimática , Glucocorticoides/farmacologia , Humanos , Hidroxicloroquina/farmacologia , Oxirredutases Intramoleculares/metabolismo , Metotrexato/farmacologia , Osteoartrite do Joelho/tratamento farmacológico , Cultura Primária de Células , Prostaglandina-E Sintases , Reação em Cadeia da Polimerase em Tempo Real , Sulfassalazina/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...