RESUMEN
One of the main goals of recent bioinorganic chemistry studies has been to design and synthesize novel substances to treat human diseases. The promising compounds are metal-based and metal ion binding components such as vanadium-based compounds. The potential anticancer action of vanadium-based compounds is one of area of investigation in this field. In this study, we present five oxovanadium(IV) and dioxovanadium(V) complexes as potential PTP1B inhibitors with anticancer activity against the MCF-7 breast cancer cell line, the triple negative MDA-MB-231 breast cancer cell line, and the human keratinocyte HaCaT cell line. We observed that all tested compounds were effective inhibitors of PTP1B, which correlates with anticancer activity. [VO(dipic)(dmbipy)]·2 H2O (Compound 4) and [VOO(dipic)](2-phepyH)·H2O (Compound 5) possessed the greatest inhibitory effect, with IC50 185.4 ± 9.8 and 167.2 ± 8.0 nM, respectively. To obtain a better understanding of the relationship between the structure of the examined compounds and their activity, we performed a computer simulation of their binding inside the active site of PTP1B. We observed a stronger binding of complexes containing dipicolinic acid with PTP1B. Based on our simulations, we suggested that the studied complexes exert their activity by stabilizing the WPD-loop in an open position and limiting access to the P-loop.
Asunto(s)
Neoplasias de la Mama , Compuestos Organometálicos , Simulación por Computador , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Compuestos Organometálicos/química , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Vanadio/química , Vanadio/farmacologíaRESUMEN
Breast cancer is the most common cancer of women-it affects more than 2 million women worldwide. PTP1B phosphatase can be one of the possible targets for new drugs in breast cancer therapy. In this paper, we present new curcumin derivatives featuring a 4-piperidone ring as PTP1B inhibitors and ROS inducers. We performed cytotoxicity analysis for twelve curcumin derivatives against breast cancer MCF-7 and MDA-MB-231 cell lines and the human keratinocyte HaCaT cell line. Furthermore, because curcumin is a known antioxidant, we assessed antioxidant effects in its derivatives. For the most potent cytotoxic compounds, we determined intracellular ROS and PTP1B phosphatase levels. Moreover, for curcumin and its derivatives, we performed real-time microscopy to observe the photosensitizing effect. Finally, computational analysis was performed for the curcumin derivatives with an inhibitory effect against PTP1B phosphatase to assess the potential binding mode of new inhibitors within the allosteric site of the enzyme. We observed that two tested compounds are better anticancer agents than curcumin. Moreover, we suggest that blocking the -OH group in phenolic compounds causes an increase in the cytotoxicity effect, even at a low concentration. Furthermore, due to this modification, a higher level of ROS is induced, which correlates with a lower level of PTP1B.
Asunto(s)
Neoplasias de la Mama , Curcumina , Citotoxinas/farmacología , Proteínas de Neoplasias/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Proteolisis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/enzimología , Curcumina/análogos & derivados , Curcumina/farmacología , Femenino , Humanos , Células MCF-7RESUMEN
Green tea (Camellia sinesis) is widely known for its anticancer and anti-inflammatory properties. Among the biologically active compounds contained in Camellia sinesis, the main antioxidant agents are catechins. Recent scientific research indicates that the number of hydroxyl groups and the presence of characteristic structural groups have a major impact on the antioxidant activity of catechins. The best source of these compounds is unfermented green tea. Depending on the type and origin of green tea leaves, their antioxidant properties may be uneven. Catechins exhibit the strong property of neutralizing reactive oxygen and nitrogen species. The group of green tea catechin derivatives includes: epicatechin, epigallocatechin, epicatechin gallate and epigallocatechin gallate. The last of these presents the most potent anti-inflammatory and anticancer potential. Notably, green tea catechins are widely described to be efficient in the prevention of lung cancer, breast cancer, esophageal cancer, stomach cancer, liver cancer and prostate cancer. The current review aims to summarize the potential anticancer effects and molecular signaling pathways of major green tea catechins. It needs to be clearly emphasized that green tea as well as green tea catechols cannot replace the standard chemotherapy. Nonetheless, their beneficial effects may support the standard anticancer approach.
Asunto(s)
Antioxidantes/farmacología , Catequina/química , Té/química , Animales , Antiinflamatorios/farmacología , Anticarcinógenos/farmacología , Catequina/análogos & derivados , Fermentación , Humanos , Células Madre Neoplásicas/efectos de los fármacos , Polifenoles/química , PronósticoRESUMEN
2-Methoxyestradiol is one of the natural 17ß-estradiol derivatives and a potential novel anticancer agent currently being under evaluation in advanced phases of clinical trials. However, the mechanism of anticancer action of 2-methoxyestradiol has not been yet fully established. In our previous studies we have demonstrated that 2-methoxyestradiol selectively induces the expression and nuclear translocation of neuronal nitric oxide synthase in osteosarcoma 143B cells. Heat shock proteins (Hsps) are factors involved in the regulation of expression and activity of nitric oxide synthases. Herein, we chose osteosarcoma cell lines differed in metastatic potential, metastatic 143B and highly metastatic MG63.2 cells, in order to further investigate the anticancer mechanism of 2-methoxyestradiol. The current study aimed to determine the role of major heat shock proteins, Hsp90 and Hsp70 in 2-methoxyestradiol-induced osteosarcoma cell death. We focused on the implication of Hsp90 and Hsp70 in control under expression of neuronal nitric oxide synthase, localization of the enzyme, and further generation of nitro-oxidative stress. To give the insight into the role of Hsp90 in regulation of anticancer efficacy of 2-methoxyestradiol, we used geldanamycin as a potent Hsp90 inhibitor. Herein, we evidenced that inhibition of Hsp90 controls the protein expression of 2-methoxyestradiol-induced neuronal nitric oxide synthase and inhibits enzyme nuclear translocation. We propose that decreased level of neuronal nitric oxide synthase protein after a combined treatment with 2-methoxyestradiol and geldanamycin is directly associated with the accompanying upregulation of Hsp70 and downregulation of Hsp90. This interaction resulted in abrogation of anticancer efficacy of 2-methoxyestradiol by geldanamycin.
Asunto(s)
2-Metoxiestradiol/farmacología , Benzoquinonas/farmacología , Neoplasias Óseas/patología , Interacciones Farmacológicas , Proteínas HSP70 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Lactamas Macrocíclicas/farmacología , Osteosarcoma/patología , Animales , Antibióticos Antineoplásicos/farmacología , Antineoplásicos/farmacología , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Modelos Biológicos , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/metabolismoRESUMEN
Elevated levels of reactive nitrogen species, alteration in redox balance and deregulated redox signaling are common hallmarks of cancer progression and chemoresistance. However, depending on the cellular context, distinct reactive nitrogen species are also hypothesized to mediate cytotoxic activity and are thus used in anticancer therapies. We present here the dual face of nitric oxide and its derivatives in cancer biology. Main derivatives of nitric oxide, such as nitrogen dioxide and peroxynitrite cause cell death by inducing protein and lipid peroxidation and/or DNA damage. Moreover, they control the activity of important protein players within the pro- and anti-apoptotic signaling pathways. Thus, the control of intracellular reactive nitrogen species may become a sophisticated tool in anticancer strategies.
Asunto(s)
Neoplasias/tratamiento farmacológico , Donantes de Óxido Nítrico/uso terapéutico , Óxido Nítrico/metabolismo , Animales , Línea Celular Tumoral , Daño del ADN/efectos de los fármacos , Humanos , Nanopartículas del Metal/química , Nanopartículas del Metal/uso terapéutico , Mitocondrias/efectos de los fármacos , Óxido Nítrico/química , Donantes de Óxido Nítrico/farmacología , Ácido Peroxinitroso/química , Ácido Peroxinitroso/metabolismo , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Proteínas/química , Proteínas/metabolismoRESUMEN
Beneficial effects of natural plant polyphenols on the human body have been evaluated in a number of scientific research projects. Bioactive polyphenols are natural compounds of various chemical structures. Their sources are mostly fruits, vegetables, nuts and seeds, roots, bark, leaves of different plants, herbs, whole grain products, processed foods (dark chocolate), as well as tea, coffee, and red wine. Polyphenols are believed to reduce morbidity and/or slow down the development of cardiovascular and neurodegenerative diseases as well as cancer. Biological activity of polyphenols is strongly related to their antioxidant properties. They tend to reduce the pool of reactive oxygen species as well as to neutralize potentially carcinogenic metabolites. A broad spectrum of health-promoting properties of plant polyphenols comprises antioxidant, anti-inflammatory, anti-allergic, anti-atherogenic, anti-thrombotic, and anti-mutagenic effects. Scientific studies present the ability of polyphenols to modulate the human immune system by affecting the proliferation of white blood cells, and also the production of cytokines or other factors that participate in the immunological defense. The aim of the review is to focus on polyphenols of olive oil in context of their biological activities.
Asunto(s)
Aceite de Oliva/química , Aceite de Oliva/farmacología , Extractos Vegetales/química , Extractos Vegetales/farmacología , Polifenoles/química , Polifenoles/farmacología , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/uso terapéutico , Antioxidantes/química , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Humanos , Olea/química , Aceite de Oliva/uso terapéutico , Fitoquímicos/química , Extractos Vegetales/uso terapéutico , Hojas de la Planta/química , Polifenoles/uso terapéuticoRESUMEN
Deregulation of serine and glycine metabolism, have been identified to function as metabolic regulators in supporting tumor cell growth. The role of serine and glycine in regulation of cancer cell proliferation is complicated, dependent on concentrations of amino acids and tissue-specific. D-serine and glycine are coagonists of N-methyl-D-aspartate (NMDA) receptor subunit GRIN1. Importantly, NMDA receptors are widely expressed in cancer cells and play an important role in regulation of cell death, proliferation, and metabolism of numerous malignancies. The aim of the present work was to associate the metabolism of glycine and D-serine with the anticancer activity of 2-methoxyestradiol. 2-methoxyestradiol is a potent anticancer agent but also a physiological 17ß- estradiol metabolite. In the study we have chosen two malignant cell lines expressing functional NMDA receptors, that is osteosarcoma 143B and breast cancer MCF7. We used MTS assay, migration assay, flow cytometric analyses, Western blotting and immunoprecipitation techniques as well as molecular modeling studies. We have demonstrated the extensive crosstalk between the deregulated metabolic network and cancer cell signaling. Herein, we observed an anticancer effect of high concentrations of glycine and D-serine in osteosarcoma cells. In contrast, the amino acids when used at low, physiological concentrations induced the proliferation and migration of osteosarcoma cells. Importantly, the pro-cancergogenic effects of both glycine and D-serine where abrogated by the usage of 2-methoxyestradiol at both physiological and pharmacological relevant concentrations. The obtained data confirmed that 2-methoxyestradiol may be a physiological anticancer molecule.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias Óseas/tratamiento farmacológico , Metabolismo Energético/efectos de los fármacos , Estradiol/análogos & derivados , Glicina/farmacología , Proteínas del Tejido Nervioso/efectos de los fármacos , Osteosarcoma/tratamiento farmacológico , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Serina/farmacología , Moduladores de Tubulina/farmacología , 2-Metoxiestradiol , Antineoplásicos/química , Antineoplásicos/metabolismo , Sitios de Unión , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Estradiol/química , Estradiol/metabolismo , Estradiol/farmacología , Femenino , Glicina/metabolismo , Humanos , Células MCF-7 , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/metabolismo , Óxido Nítrico Sintasa de Tipo I/metabolismo , Osteosarcoma/metabolismo , Osteosarcoma/patología , Unión Proteica , Dominios Proteicos , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/metabolismo , Serina/metabolismo , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Factores de Tiempo , Moduladores de Tubulina/química , Moduladores de Tubulina/metabolismoRESUMEN
Yersinia sp. bacteria owe their viability and pathogenic virulence to the YopH factor, which is a highly active bacterial protein tyrosine phosphatase. Inhibition of YopH phosphatase results in the lack of Yersinia sp. pathogenicity. We have previously described that aurintricarboxylic acid inhibits the activity of YopH at nanomolar concentrations and represents a unique mechanism of YopH inactivation due to a redox process. This work is a continuation of our previous studies. Here we show that modifications of the structure of aurintricarboxylic acid reduce the ability to inactivate YopH and lead to higher cytotoxicity. In the present paper we examine the inhibitory properties of aurintricarboxylic acid analogues, such as eriochrome cyanine R (ECR) and pararosaniline. Computational docking studies we report here indicate that ATA analogues are not precluded to bind in the YopH active site and in all obtained binding conformations ECR and pararosaniline bind to YopH active site. The free binding energy calculations show that ECR has a stronger binding affinity to YopH than pararosaniline, which was confirmed by experimental YopH enzymatic activity studies. We found that ATA analogues can reversibly reduce the enzymatic activity of YopH, but possess weaker inhibitory properties than ATA. The ATA analogues induced inactivation of YopH is probably due to oxidative mechanism, as pretreatment with catalase prevents from inhibition. We also found that ATA analogues significantly decrease the viability of macrophage cells, especially pararosaniline, while ATA reveals only slight effect on cell viability.
Asunto(s)
Ácido Aurintricarboxílico/análogos & derivados , Proteínas de la Membrana Bacteriana Externa/química , Bencenosulfonatos/química , Proteínas Tirosina Fosfatasas/química , Colorantes de Rosanilina/química , Toluidinas/química , Yersinia/efectos de los fármacos , Animales , Ácido Aurintricarboxílico/química , Ácido Aurintricarboxílico/farmacología , Proteínas de la Membrana Bacteriana Externa/antagonistas & inhibidores , Bencenosulfonatos/farmacología , Dominio Catalítico/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Ratones , Modelos Moleculares , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Unión Proteica , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Colorantes de Rosanilina/farmacología , Toluidinas/farmacología , Yersinia/enzimologíaRESUMEN
BACKGROUND/AIMS: Protein tyrosine phosphatases are crucial enzymes controlling numerous physiological and pathophysiological events and can be regulated by oxidation of the catalytic domain cysteine residue. Peracids are highly oxidizing compounds, and thus may induce inactivation of PTPs. The aim of the present study was to evaluate the inhibitory effect of peracids with different length of hydrocarbon chain on the activity of selected PTPs. METHODS: The enzymatic activity of human CD45, PTP1B, LAR, bacterial YopH was assayed under the cell-free conditions, and activity of cellular CD45 in human Jurkat cell lysates. The molecular docking and molecular dynamics were performed to evaluate the peracids binding to the CD45 active site. RESULTS: Here we demonstrate that peracids reduce enzymatic activity of recombinant CD45, PTP1B, LAR, YopH and cellular CD45. Our studies indicate that peracids are more potent inhibitors of CD45 than hydrogen peroxide (with an IC50 value equal to 25 nM for peroctanoic acid and 8 µM for hydrogen peroxide). The experimental data show that the inactivation caused by peracids is dependent on hydrocarbon chain length of peracids with maximum inhibitory effect of medium-chain peracids (C8-C12 acyl chain), which correlates with calculated binding affinities to the CD45 active site. CONCLUSION: Peracids are potent inhibitors of PTPs with the strongest inhibitory effect observed for medium-chain peracids.
Asunto(s)
Proteínas de la Membrana Bacteriana Externa/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Antígenos Comunes de Leucocito/antagonistas & inhibidores , Peróxidos/química , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/antagonistas & inhibidores , Proteínas de la Membrana Bacteriana Externa/química , Dominio Catalítico , Extractos Celulares/química , Pruebas de Enzimas , Humanos , Peróxido de Hidrógeno/química , Células Jurkat , Cinética , Antígenos Comunes de Leucocito/química , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Ácido Peracético/química , Proteínas Tirosina Fosfatasas/química , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/química , Proteínas Recombinantes/químicaRESUMEN
Hydrogen peroxide is an important regulator of protein tyrosine phosphatase activity via reversible oxidation. However, the role of iron in this reaction has not been yet elucidated. Here we compare the influence of hydrogen peroxide and the ferrous iron (reagent for Fenton reaction) on the enzymatic activity of recombinant CD45, LAR, PTP1B phosphatases and cellular CD45 in Jurkat cells. The obtained results show that ferrous iron (II) is potent inhibitor of CD45, LAR and PTP1B, but the inhibitory effect is concentration dependent. We found that the higher concentrations of ferrous iron (II) increase the inactivation of CD45, LAR and PTP1B phosphatase caused by hydrogen peroxide, but the addition of the physiological concentration (500 nM) of ferrous iron (II) has even a slightly preventive effect on the phosphatase activity against hydrogen peroxide.
Asunto(s)
Compuestos Ferrosos/farmacología , Peróxido de Hidrógeno/farmacología , Antígenos Comunes de Leucocito/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 1/genética , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/genética , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Regulación de la Expresión Génica , Humanos , Células Jurkat , Antígenos Comunes de Leucocito/antagonistas & inhibidores , Antígenos Comunes de Leucocito/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/antagonistas & inhibidores , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/metabolismo , Transducción de SeñalRESUMEN
A randomized prospective clinical study performed on a group of 74 pregnant women (43 presenting with severe preeclampsia) proved that urinary levels of 15-F(2t)-isoprostane were significantly higher in preeclamptic patients relative to the control (3.05 vs. 2.00 ng/mg creatinine). Surprisingly enough, plasma levels of 25-hydroxyvitamin D3 in both study groups were below the clinical reference range with no significant difference between the groups. In vitro study performed on isolated placental mitochondria and placental cell line showed that suicidal self-oxidation of cytochrome P450scc may lead to structural disintegration of heme, potentially contributing to enhancement of oxidative stress phenomena in the course of preeclampsia. As placental cytochrome P450scc pleiotropic activity is implicated in the metabolism of free radical mediated arachidonic acid derivatives as well as multiple Vitamin D3 hydroxylations and progesterone synthesis, we propose that Vitamin D3 might act as a competitive inhibitor of placental cytochrome P450scc preventing the production of lipid peroxides or excess progesterone synthesis, both of which may contribute to the etiopathogenesis of preeclampsia. The proposed molecular mechanism is in accord with the preliminary clinical observations on the surprisingly high efficacy of high-dose Vitamin D3 supplementation in prevention and treatment of preeclampsia.
Asunto(s)
Calcifediol/farmacología , Peroxidación de Lípido/efectos de los fármacos , Preeclampsia/prevención & control , Vitaminas/farmacología , Adulto , Ácido Araquidónico/metabolismo , Calcifediol/uso terapéutico , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/metabolismo , Femenino , Humanos , Placenta/metabolismo , Preeclampsia/tratamiento farmacológico , Embarazo , Vitaminas/uso terapéuticoRESUMEN
OBJECTIVE: 2-Methoxyestradiol, one of the natural 17ß-estradiol derivatives, is a novel, potent anticancer agent currently being evaluated in advanced phases of clinical trials. The main goal of the study was to investigate the anticancer activity of 2-methoxy-estradiol towards osteosarcoma cells and its possible neurodegenerative effects. We used an experimental model of neurotoxicity and anticancer activity of the physiological agent, 2-methoxyestradiol. Thus, we used highly metastatic osteosarcoma 143B and mouse immortalized hippocampal HT22 cell lines. The cells were treated with pharmacological (1 µM, 10 µM) concentrations of 2-methoxyestradiol. EXPERIMENTAL: Neuronal nitric oxide synthase and 3-nitrotyrosine protein levels were determined by western blotting. Cell viability and induction of cell death were measured by MTT and PI/Annexin V staining and a DNA fragmentation ELISA kit, respectively. Intracellular levels of nitric oxide were determined by flow cytometry. RESULTS: Here we demonstrated that the signaling pathways of neurodegenerative diseases and cancer may overlap. We presented evidence that 2-methoxyestradiol, in contrast to 17ß-estradiol, specifically affects neuronal nitric oxide synthase and augments 3-nitrotyrosine level leading to osteosarcoma and immortalized hippocampal cell death. CONCLUSIONS: We report the dual facets of 2-methoxyestradiol, that causes cancer cell death, but on the other hand may play a key role as a neurotoxin.
Asunto(s)
Antineoplásicos/farmacología , Estradiol/análogos & derivados , Óxido Nítrico Sintasa de Tipo I/genética , 2-Metoxiestradiol , Antineoplásicos/toxicidad , Apoptosis , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Inducción Enzimática/efectos de los fármacos , Estradiol/farmacología , Estradiol/toxicidad , Hipocampo/patología , Humanos , Neuronas/efectos de los fármacos , Neuronas/fisiología , Óxido Nítrico Sintasa de Tipo I/biosíntesis , Osteosarcoma/tratamiento farmacológico , Estrés OxidativoRESUMEN
Purpose: Citric acid (CA) is a tricarboxylic acid with antioxidant and antimicrobial properties. Based on previous studies, the small compound with its three carboxylic groups can be considered a protein tyrosine phosphatase inhibitor. YopH, a protein tyrosine phosphatase, is an essential virulence factor in Yersinia bacteria. Materials and Methods: We performed enzymatic activity assays of YopH phosphatase after treatment with citric acid in comparison with the inhibitory compound trimesic acid, which has a similar structure. We also measured the cytotoxicity of these compounds in Jurkat T E6.1 and macrophage J774.2 cell lines. We performed molecular docking analysis of the binding of citric acid molecules to YopH phosphatase. Results: Citric acid and trimesic acid reversibly reduced the activity of YopH enzyme and decreased the viability of Jurkat and macrophage cell lines. Importantly, these two compounds showed greater inhibitory properties against bacterial YopH activity than against human CD45 phosphatase activity. Molecular docking simulations confirmed that citric acid could bind to YopH phosphatase. Conclusion: Citric acid, a known antioxidant, can be considered an inhibitor of bacterial phosphatases.
Asunto(s)
Antioxidantes , Proteínas Tirosina Fosfatasas , Ácidos Tricarboxílicos , Humanos , Simulación del Acoplamiento Molecular , Proteínas Tirosina Fosfatasas/química , Proteínas Tirosina Fosfatasas/metabolismo , TirosinaRESUMEN
Graphene and graphene-based materials have attracted growing interest for potential applications in medicine because of their good biocompatibility, cargo capability and possible surface functionalizations. In parallel, prototypic graphene-based devices have been developed to diagnose, imaging and track tumor growth in cancer patients. There is a growing number of reports on the use of graphene and its functionalized derivatives in the design of innovative drugs delivery systems, photothermal and photodynamic cancer therapy, and as a platform to combine multiple therapies. The aim of this review is to introduce the latest scientific achievements in the field of innovative composite graphene materials as potentially applied in cancer therapy. The "Technology and Innovation Roadmap" published in the Graphene Flagship indicates, that the first anti-cancer drugs using graphene and graphene-derived materials will have appeared on the market by 2030. However, it is necessary to broaden understanding of graphene-based material interactions with cellular metabolism and signaling at the functional level, as well as toxicity. The main aspects of further research should elucidate how treatment methods (e.g., photothermal therapy, photodynamic therapy, combination therapy) and the physicochemical properties of graphene materials influence their ability to modulate autophagy and kill cancer cells. Interestingly, recent scientific reports also prove that graphene nanocomposites modulate cancer cell death by inducing precise autophagy dysfunctions caused by lysosome damage. It turns out as well that developing photothermal oncological treatments, it should be taken into account that near-infrared-II radiation (1000-1500 nm) is a better option than NIR-I (750-1000 nm) because it can penetrate deeper into tissues due to less scattering at longer wavelengths radiation.
Asunto(s)
Antineoplásicos , Grafito , Neoplasias , Grafito/química , Humanos , Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Sistemas de Liberación de Medicamentos/métodos , Fotoquimioterapia/métodos , Autofagia/efectos de los fármacos , Animales , Nanocompuestos/química , Nanocompuestos/uso terapéutico , NanomedicinaRESUMEN
Introduction: Solid lipid nanoparticles (SLN) have been considered lately as promising drug delivery system in treatment of many human diseases including cancers. We previously studied potential drug compounds that were effective inhibitors of PTP1B phosphatase - possible target for breast cancer treatment. Based on our studies, two complexes were selected for encapsulation into the SLNs, the compound 1 ([VO(dipic)(dmbipy)] · 2 H2O) and compound 2 ([VOO(dipic)](2-phepyH) · H2O). Here, we investigate the effect of encapsulation of those compounds on cell cytotoxicity against MDA-MB-231 breast cancer cell line. The study also included the stability evaluation of the obtained nanocarriers with incorporated active substances and characterization of their lipid matrix. Moreover, the cell cytotoxicity studies against the MDA-MB-231 breast cancer cell line in comparison and in combination with vincristine have been performed. Wound healing assay was carried out to observe cell migration rate. Methods: The properties of the SLNs such as particle size, zeta potential (ZP), and polydispersity index (PDI) were investigated. The morphology of SLNs was observed by scanning electron microscopy (SEM), while the crystallinity of the lipid particles was analyzed by differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The cell cytotoxicity of complexes and their encapsulated forms was carried out against MDA-MB-231 breast cancer cell line using standard MTT protocols. The wound healing assay was performed using live imaging microscopy. Results: SLNs with a mean size of 160 ± 25 nm, a ZP of -34.00 ± 0.5, and a polydispersity index of 30 ± 5% were obtained. Encapsulated forms of compounds showed significantly higher cytotoxicity also in co-incubation with vincristine. Moreover, our research shows that the best compound was complex 2 encapsulated into lipid nanoparticles. Conclusion: We observed that encapsulation of studied complexes into SLNs increases their cell cytotoxicity against MDA-MB-231 cell line and enhanced the effect of vincristine.
Asunto(s)
Neoplasias de la Mama , Nanopartículas , Humanos , Femenino , Vincristina , Lípidos/química , Células MDA-MB-231 , Nanopartículas/química , Neoplasias de la Mama/tratamiento farmacológico , Tamaño de la Partícula , Portadores de Fármacos/químicaRESUMEN
The review is focused on the bacterial protein tyrosine phosphatases (PTPs) utilized by bacteria as virulence factors necessary for pathogenicity. The inhibition of bacterial PTPs could contribute to the arrest of the bacterial infection process. This mechanism could be utilized in the design of antimicrobial therapy as adjuvants to antibiotics. The review summaries knowledge on pathogenic bacterial protein tyrosine phosphatases (PTPs) involved in infection process, such as: PTPA and PTPB from Staphylococcus aureus and Mycobacterium tuberculosis; SptP from Salmonella typhimurium; YopH from Yersinia sp. and TbpA from Pseudomonas aeruginosa. The review focuses also on the potential inhibitory compounds of bacterial virulence factors and inhibitory mechanisms such as the reversible oxidation of tyrosine phosphatases.
RESUMEN
Gliomas are the most prevalent primary tumors of the central nervous system (CNS), accounting for over fifty percent of all primary intracranial neoplasms. Glioblastoma (GBM) is the most prevalent form of malignant glioma and is often incurable. The main distinguishing trait of GBM is the presence of hypoxic regions accompanied by enhanced angiogenesis. 2-Methoxyestradiol (2-ME) is a well-established antiangiogenic and antiproliferative drug. In current clinical studies, 2-ME, known as Panzem, was examined for breast, ovarian, prostate, and multiple myeloma. The SW1088 grade III glioma cell line was treated with pharmacological and physiological doses of 2-ME. The induction of apoptosis and necrosis, oxidative stress, cell cycle arrest, and mitochondrial membrane potential were established by flow cytometry. Confocal microscopy was used to detect DNA damage. The Western blot technique determined the level of nitric oxide synthase and heat shock proteins. Here, for the first time, 2-ME is shown to induce nitro-oxidative stress with the concomitant modulation of heat shock proteins (HSPs) in the SW1088 grade III glioma cell line. Crucial therapeutic strategies for GMB should address both cell proliferation and angiogenesis, and due to the above, 2-ME seems to be a perfect candidate for GBM therapy.
RESUMEN
Lung cancer is one of the most common cancers worldwide, causing nearly one million deaths each year. Herein, we present the effect of 2-methoxyestradiol (2-ME), the endogenous metabolite of 17ß-estradiol (E2), on non-small cell lung cancer (NSCLC) cells. We observed that 2-ME reduced the viability of lung adenocarcinoma in two-dimensional (2D) and three-dimensional (3D) spheroidal A549 cell culture models. Molecular modeling was carried out aiming to visualize amino acid residues within binding pockets of the acyl-protein thioesterases, namely 1 (APT1) and 2 (APT2), and thus to identify which ones were more likely involved in the interaction with 2-ME. Our findings suggest that 2-ME acts as an APT1 inhibitor enhancing protein palmitoylation and oxidative stress phenomena in the lung cancer cell. In order to support our data, metabolomics of blood serum from NSCLC patients was also performed. Moreover, computational analysis suggests that 2-ME as compared to other estrogen metabolism intermediates is relatively safe in terms of its possible non-receptor bioactivity within healthy human cells due to a very low electrophilic potential and hence no substantial risk of spontaneous covalent modification of biologically protective nucleophiles. We propose that 2-ME can be used as a selective tumor biomarker in the course of certain types of lung cancers and possibly as a therapeutic adjuvant or neoadjuvant.
RESUMEN
We have designed a useful method of assessing reactive oxygen species generation in biological fluids. The novel assay utilizes tyrosine phosphatase CD45 as a biosensor of oxidative stress. Applying this new method, we examined oxygen species generation in the following cell culture media: RPMI 1640, DMEM, DMEM enriched with pyruvate and MEM. We discovered that the media (especially RPMI 1640) significantly reduced the activity of protein tyrosine phosphatase. The media-caused inactivation of CD45 was reversible after treatment with dithiothreitol being a powerful reducing agent. Interestingly, the media supplemented with catalase did not exhibit any inhibitory effect on CD45 activity which suggests a hydrogen peroxide-mediated mechanism of the enzyme inactivation. In addition to that, we assessed the impact of oxidative stress level on the activity of CD45 as measured in Jurkat cells cultured in RPMI 1640 either exposed or not exposed to the light of laminar flow cabinet fluorescent lamp. We found that Jurkat cells that were exposed to light displayed ca. 20% lower activity of CD45 than the cells protected against the light. The obtained results indicate that production of hydrogen peroxide in the medium leading to inhibition of CD45 was light-dependent, and that careful protection of cell culture media from the light may help to prevent the artifact in cell studies. Hydrogen peroxide, responsible for CD45 inactivation, can be generated in cell culture media after exposition to light due to photoreactive amino acids present in the media.
Asunto(s)
Técnicas Biosensibles , Medios de Cultivo/química , Peróxido de Hidrógeno/análisis , Antígenos Comunes de Leucocito/antagonistas & inhibidores , Técnicas de Cultivo de Célula , Humanos , Peróxido de Hidrógeno/metabolismo , Células Jurkat , Antígenos Comunes de Leucocito/análisis , Antígenos Comunes de Leucocito/genética , Estrés OxidativoRESUMEN
Mitochondria, as "power house of the cell", are crucial players in cell pathophysiology. Beyond adenosine triphosphate (ATP) production, they take part in a generation of reactive oxygen species (ROS), regulation of cell signaling and cell death. Dysregulation of mitochondrial dynamics may lead to cancers and neurodegeneration; however, the fusion/fission cycle allows mitochondria to adapt to metabolic needs of the cell. There are multiple data suggesting that disturbed mitochondrial homeostasis can lead to Parkinson's disease (PD) development. 2-methoxyestradiol (2-ME), metabolite of 17ß-estradiol (E2) and potential anticancer agent, was demonstrated to inhibit cell growth of hippocampal HT22 cells by means of nitric oxide synthase (NOS) production and oxidative stress at both pharmacologically and also physiologically relevant concentrations. Moreover, 2-ME was suggested to inhibit mitochondrial biogenesis and to be a dynamic regulator. This review is a comprehensive discussion, from both scientific and clinical point of view, about the influence of 2-ME on mitochondria and its plausible role as a modulator of neuron survival.