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Cutaneous T cell lymphoma (CTCL) is a varied group of neoplasms that affects the skin. Acquired resistance against chemotherapeutic drugs and associated toxic side effects are limitations that warrant search for novel drugs against CTCL. Embelin (EMB) is a naturally occurring benzoquinone derivative that has gained attention owing to its anticancer pharmacological actions and nontoxic nature. We assessed the anticancer activity of EMB against CTCL cell lines, HuT78, and H9. EMB inhibited viability of CTCL cells in a dose-dependent manner. EMB activated extrinsic and intrinsic pathways of apoptosis as shown by the activation of initiator and executioner caspases. EMB-induced apoptosis also involved suppression of inhibitors of apoptosis, XIAP, cIAP1, and cIAP2. PARP cleavage and upregulation of pH2AX indicated DNA damage induced by EMB. In conclusion, we characterized a novel apoptosis-inducing activity of EMB against CTCL cells, implicating EMB as a potential therapeutic agent against CTCL.
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Linfoma Cutáneo de Células T , Neoplasias Cutáneas , Humanos , Apoptosis , Linfoma Cutáneo de Células T/tratamiento farmacológico , Linfoma Cutáneo de Células T/genética , Linfoma Cutáneo de Células T/metabolismo , Benzoquinonas/farmacología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Línea Celular , Línea Celular TumoralRESUMEN
Targeted therapy, such as tyrosine kinase inhibitors (TKIs), has been approved to manage various cancer types. However, TKI-induced cardiotoxicity is a limiting factor for their use. This issue has raised the need for investigating potential cardioprotective techniques to be combined with TKIs. Ribosomal S6-kinases (RSKs) are a downstream effector of the mitogen-activated-protein-kinase (MAPK) pathway; specific RSK isoforms, such as RSK1 and RSK2, have been expressed in cancer cells, in which they increase tumour proliferation. Selective targeting of those isoforms would result in tumour suppression. Moreover, activation of RSKs expressed in the heart has resulted in cardiac hypertrophy and arrhythmia; thus, inhibiting RSKs would result in cardio-protection. This review article presents an overview of the usefulness of RSK inhibitors that can be novel agents to be assessed in future research for their effect in reducing cancer proliferation, as well as protecting the heart from cardiotoxicity induced by TKIs.
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The precise mechanism of macrolide antibiotic azithromycin (AZM) mediated CD4+ T cell suppression is not fully understood. Given the crucial role of co-stimulatory signaling in T-lymphocyte function, we tested in vitro effects of AZM on two of the most extensively investigated costimulatory molecules, ICOS and OX40 in context to CD4+ T cell proliferation. Using multi-color flow cytometry approach on TCR-activated healthy donor peripheral blood mononuclear cells, we observed a marked reduction in the frequencies and surface expression of ICOS and OX40 receptors following AZM treatment. Functionally, in contrast to ICOS- and OX40- CD3+ CD4+ T cells, AZM treated ICOS+ and OX40+ displayed profound reduction in cell proliferation. Furthermore, AZM treated T cells displaying reduced levels of ICOS and OX40 found to be associated with suppressed mTOR activity as detected by phosphorylation levels of S6 ribosomal protein. This study provides new insights on potential mechanism of AZM mediated inhibition of T cell proliferation by targeting costimulatory pathways.
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INTRODUCTION: Pharmaceutical biotechnology involves using the principles of biotechnology to develop drugs. With the rapid increase in biopharmaceutical products being developed and approved for use, educating pharmacy students about biotechnological products becomes paramount. However, there is a scarcity in the literature exploring biotechnology content in pharmacy education. This paper aims to explore and discuss previously published studies on biotechnology education in pharmacy curricula and will provide a brief overview of biotechnology content offered in pharmacy schools in Arab countries. PERSPECTIVE: The majority of pharmacy schools in the United States and Europe offer biotechnology-related content within the curriculum as part of other courses. It has also been reported that biotechnology content is taught in 22 pharmacy schools in Arab countries. In general, biotechnology content is mostly taught as part of other pharmacy courses and is often provided as compulsory content. Including pharmaceutical biotechnology concepts in pharmacy curriculum has positive impact on pharmacy students as it increases their knowledge of biotechnology and their interest in the topic. IMPLICATION: Pharmaceutical biotechnology is an important field in which pharmacy graduates should be knowledgeable. However, there is a need to explore biotechnology content offered in pharmacy schools in other parts of the world in order to have an understanding of how different pharmacy programs prepare their students for practice. The information currently available in the literature is not enough to determine the usefulness of pharmaceutical biotechnology content currently offered to prepare pharmacists for practice. This highlights the need for further research in the area.
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Árabes , Farmacia , Humanos , Biotecnología , Curriculum , Facultades de Farmacia , Estados UnidosRESUMEN
Diabetes mellitus (DM)-induced cardiac morbidities have been the leading cause of death among diabetic patients. Recently, sodium-glucose cotransporter-2 (SGLT-2) inhibitors including empagliflozin (EMPA), which have been approved for the treatment of DM, have gained attention for their cardioprotective effect. The mechanism by which SGLT-2 inhibitors exert their cardioprotective effect remains unclear. Recent studies have suggested that EMPA exerts its cardioprotective effect by inhibiting the Na+/H+ exchanger (NHE), a group of membrane proteins that regulate intracellular pH and cell volume. Increased activity and expression of NHE isoform 1 (NHE1), the predominant isoform expressed in the heart, leads to cardiac hypertrophy. p90 ribosomal s6 kinase (p90 RSK) has been demonstrated to stimulate NHE1 activity. In our study, H9c2 cardiomyoblasts were treated with angiotensin II (ANG) to activate NHE1 and generate a hypertrophic model. We aimed to understand whether EMPA reverses the ANG-induced hypertrophic response and to elucidate the molecular pathway contributing to the cardioprotective effect of EMPA. Our study demonstrated that ANG-induced hypertrophy of H9c2 cardiomyoblasts is accompanied with increased SGLT-1 and NHE1 protein expression, an effect which is prevented in the presence of EMPA. EMPA reduces ANG-induced hypertrophy through the inhibition of SGLT-1 and NHE1 expression.
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Angiotensina II , Miocitos Cardíacos , Angiotensina II/metabolismo , Angiotensina II/farmacología , Compuestos de Bencidrilo , Cardiomegalia/inducido químicamente , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/metabolismo , Glucósidos/farmacología , Humanos , Miocitos Cardíacos/metabolismoRESUMEN
Numerous studies demonstrate parallels between CVD, type 2 diabetes mellitus (T2DM) and COVID-19 pathology, which accentuate pre-existing complications in patients infected with COVID-19 and potentially exacerbate the infection course. Antidiabetic drugs such as sodium-glucose transporter-2 (SGLT-2) inhibitors have garnered substantial attention recently due to their efficacy in reducing the severity of cardiorenal disease. The effect of SGLT-2 inhibitors in patients with COVID-19 remains unclear particularly since SGLT-2 inhibitors contribute to altering the RAAS cascade activity, which includes ACE-2, the major cell entry receptor for SARS-CoV2. A study, DARE-19, was carried out to unveil the effects of SGLT-2 inhibitor treatment on comorbid disease complications and concomitant COVID-19 outcomes and demonstrated no statistical significance. However, the need for further studies is essential to provide conclusive clinical findings.
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Compuestos de Bencidrilo/uso terapéutico , COVID-19/complicaciones , Glucósidos/uso terapéutico , Sistema Renina-Angiotensina/efectos de los fármacos , Insuficiencia Respiratoria/tratamiento farmacológico , SARS-CoV-2 , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Enzima Convertidora de Angiotensina 2/fisiología , Ensayos Clínicos Fase III como Asunto , Método Doble Ciego , Reposicionamiento de Medicamentos , Cardiopatías/prevención & control , Humanos , Enfermedades Renales/prevención & control , Mitocondrias/efectos de los fármacos , Estudios Multicéntricos como Asunto , Estrés Oxidativo/efectos de los fármacos , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores Virales/fisiología , Insuficiencia Respiratoria/etiología , Transportador 2 de Sodio-Glucosa/fisiología , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacologíaRESUMEN
Previous studies have established the role of Na+/H+ exchanger isoform-1 (NHE1) and cathepsin B (Cat B) in the development of cardiomyocyte hypertrophy (CH). Both NHE1 and Cat B are activated under acidic conditions suggesting that their activities might be interrelated. The inhibition of NHE1 has been demonstrated to reduce cardiac hypertrophy but the mechanism that contributes to the anti-hypertrophic effect of NHE1 inhibition still remains unclear. H9c2 cardiomyoblasts were stimulated with Angiotensin (Ang) II in the presence and absence of N-[2-methyl-4,5-bis(methylsulphonyl)-benzoyl]-guanidine, hydrochloride (EMD, EMD 87580), an NHE1 inhibitor or CA-074Me, a Cat B inhibitor, and various cardiac hypertrophic parameters, namely cell surface area, protein content and atrial natriuretic peptide (ANP) mRNA were analyzed. EMD significantly suppressed markers of cardiomyocyte hypertrophy and inhibited Ang II stimulated Cat B protein and gene expression. Cat B is located within the acidic environment of lysosomes. Cat B proteases are released into the cytoplasm upon disintegration of the lysosomes. EMD or CA-074Me prevented the dispersal of the lysosomes induced by Ang II and reduced the ratio of LC3-II to LC3-I, a marker of autophagy. Moreover, Cat B protein expression and MMP-9 activity in the extracellular space were significantly attenuated in the presence of EMD or CA-074Me. Our study demonstrates a novel mechanism for attenuation of the hypertrophic phenotype by NHE1 inhibition that is mediated by a regression in Cat B. The inhibition of Cat B via EMD or CA-074Me attenuates the autosomal-lysosomal pathway and MMP-9 activation.
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Catepsina B/antagonistas & inhibidores , Catepsina B/metabolismo , Guanidinas/farmacología , Miocitos Cardíacos/metabolismo , Intercambiador 1 de Sodio-Hidrógeno/antagonistas & inhibidores , Intercambiador 1 de Sodio-Hidrógeno/metabolismo , Sulfonas/farmacología , Animales , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/metabolismo , Cardiomegalia/patología , Línea Celular , Dipéptidos/farmacología , Dipéptidos/uso terapéutico , Guanidinas/uso terapéutico , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Ratas , Sulfonas/uso terapéuticoRESUMEN
OBJECTIVE: Cisplatin is a standard treatment approach against lung adenocarcinoma. Resistance to cisplatin and the toxic side effects of cisplatin continue to remain a challenge. Combining drugs with different mechanisms is being investigated as a means to overcome these challenges. In ovarian cancer cells, the knockdown of RSK2 increased the sensitivity of cisplatin. RSK is a downstream mediator of the MAPK pathway that is responsible for cell survival, proliferation and migration. METHODS: Our study examined the effect of cisplatin, BI-D1870 (RSK inhibitor) or their combination on cell migration, apoptosis, autophagy and cell cycle in A549 human lung adenocarcinoma cells. KEY FINDINGS: The combination of cisplatin and BI-D1870 potentiated the antimigration rate, the activation of caspases-3 and was associated with a significant decrease in RSK1 and ERK expression when compared to cisplatin alone. The combination of cisplatin and BI-D1870 also resulted in the inhibition of LC3 II to LC3 I expression when compared to BI-D1870. The combination of cisplatin and BI-D1870 increased the number of cells in the G2/M-phase when compared to cisplatin alone. CONCLUSIONS: These findings suggest that combining cisplatin with agents that target the RSK mediated cell survival pathway, may potentiate the cisplatin effect in lung adenocarcinoma.
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Adenocarcinoma del Pulmón/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Cisplatino/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Pteridinas/farmacología , Proteínas Quinasas S6 Ribosómicas 90-kDa/antagonistas & inhibidores , Células A549 , Adenocarcinoma del Pulmón/enzimología , Adenocarcinoma del Pulmón/patología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Caspasa 3/metabolismo , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Proteínas Asociadas a Microtúbulos/metabolismo , Terapia Molecular Dirigida , Invasividad Neoplásica , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Transducción de SeñalRESUMEN
Lung cancer is one of the major causes of death worldwide. Natural molecules with anti-lung cancer potential are of a great interest and considered as very promising alternative to substitute or enhance the efficiency of the conventional drugs. Recently, algae as source of high value-added compounds are considered as very promising source of these bioactive molecules. These are secondary metabolites that consist mainly of derivatives of peptides, carbohydrates, and lipids with various structures. Accordingly, various mechanisms by which different algae molecules demonstrate attenuation of tumor angiogenesis were stated and discussed. The mode of action of the algae bioactives is closely related to their nature and chemical structure. Furthermore, this literature review considers the synergistic effect between microalgae bioactives and conventional drugs and discuss the economic feasibility of producing microalgae bioactives at large scale to conclude with some future perspectives related to algae-based drug discovery.
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Antineoplásicos/farmacología , Productos Biológicos/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Fitoquímicos/farmacología , Carbohidratos/farmacología , Descubrimiento de Drogas , Humanos , Lípidos/farmacología , Microalgas/química , Péptidos/farmacología , Fitoquímicos/química , Algas Marinas/químicaRESUMEN
Osteopontin (OPN) is recognized for its significant roles in both physiological and pathological processes. Initially, OPN was recognized as a cytokine with pro-inflammatory actions. More recently, OPN has emerged as a matricellular protein of the extracellular matrix (ECM). OPN is also known to be a substrate for proteolytic cleavage by several proteases that form an integral part of the ECM. In the adult heart under physiological conditions, basal levels of OPN are expressed. Increased expression of OPN has been correlated with the progression of cardiac remodeling and fibrosis to heart failure and the severity of the condition. The intricate process by which OPN mediates its effects include the coordination of intracellular signals necessary for the differentiation of fibroblasts into myofibroblasts, promoting angiogenesis, wound healing, and tissue regeneration. In this review, we discuss the role of OPN in contributing to the development of cardiac fibrosis and its suitability as a therapeutic target.
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Cardiomiopatías/etiología , Cardiomiopatías/metabolismo , Osteopontina/genética , Osteopontina/metabolismo , Biomarcadores , Cardiomiopatías/patología , Susceptibilidad a Enfermedades , Fibrosis , Regulación de la Expresión Génica , Cardiopatías/etiología , Cardiopatías/metabolismo , Cardiopatías/patología , Humanos , Transducción de SeñalRESUMEN
Cardiac remodeling, characterized by excessive extracellular matrix (ECM) remodeling, predisposes the heart to failure if left unresolved. Understanding the signaling mechanisms involved in excessive extracellular matrix (ECM) remodeling is necessary to identify the means to regress the development of cardiac remodeling and heart failure. Recently, hyaluronan (HA), a ubiquitously expressed glycosaminoglycan in the ECM, was shown to participate in tissue fibrosis and myofibroblast proliferation through interacting with its ubiquitously expressed cell-surface receptor, CD44. CD44 is a multifunctional transmembrane glycoprotein that serves as a cell-surface receptor for a number of ECM proteins. The mechanism by which the interaction between CD44-HA contributes to ECM and cardiac remodeling remains unknown. A previous study performed on a non-cardiac model showed that CD44-HA enhances Na+/H+ exchanger isoform-1 (NHE1) activity, causing ECM remodeling, HA metabolism and tumor invasion. Interestingly, NHE1 has been demonstrated to be involved in cardiac remodeling and myocardial fibrosis. In addition, it has previously been demonstrated that CD44 is upregulated in transgenic mouse hearts expressing active NHE-1. The role of CD44, HA and NHE1 and the cellular interplay of these factors in the ECM and cardiac remodeling is the focus of this review.
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Remodelación Atrial , Insuficiencia Cardíaca/fisiopatología , Receptores de Hialuranos/metabolismo , Ácido Hialurónico/metabolismo , Miocitos Cardíacos/fisiología , Intercambiador 1 de Sodio-Hidrógeno/metabolismo , Remodelación Ventricular , Humanos , Miocitos Cardíacos/citología , Transducción de SeñalRESUMEN
Cisplatin is a widely used chemotherapeutic agent for treatment of various cancers. However, treatment with cisplatin is associated with drug resistance and several adverse side effects such as nephrotoxicity, reduced immunity towards infections and hearing loss. A Combination of cisplatin with other drugs is an approach to overcome drug resistance and reduce toxicity. The combination therapy also results in increased sensitivity of cisplatin towards cancer cells. The mitogen activated protein kinase (MAPK) pathway in the cell, consisting of extracellular signal regulated kinase, c-Jun N-terminal kinase, p38 kinases, and downstream mediator p90 ribosomal s6 kinase (RSK); is responsible for the regulation of various cellular events including cell survival, cell proliferation, cell cycle progression, cell migration and protein translation. This review article demonstrates the role of MAPK pathway in cisplatin based therapy, illustrates different combination therapy involving cisplatin and also shows the importance of targeting MAPK family, particularly RSK, to achieve increased anticancer effect and overcome drug resistance when combined with cisplatin.
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Cisplatino/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Terapia Molecular DirigidaRESUMEN
Cardiovascular diseases are the leading cause of death worldwide. One in three cases of heart failure is due to dilated cardiomyopathy. The Na+/H+ exchanger isoform 1 (NHE1), a multifunctional protein and the key pH regulator in the heart, has been demonstrated to be increased in this condition. We have previously demonstrated that elevated NHE1 activity induced cardiac hypertrophy in vivo. Furthermore, the overexpression of active NHE1 elicited modulation of gene expression in cardiomyocytes including an upregulation of myocardial osteopontin (OPN) expression. To determine the role of OPN in inducing NHE1-mediated cardiomyocyte hypertrophy, double transgenic mice expressing active NHE1 and OPN knockout were generated and assessed by echocardiography and the cardiac phenotype. Our studies showed that hearts expressing active NHE1 exhibited cardiac remodeling indicated by increased systolic and diastolic left ventricular internal diameter and increased ventricular volume. Moreover, these hearts demonstrated impaired function with decreased fractional shortening and ejection fraction. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) mRNA was upregulated, and there was an increase in heart cell cross-sectional area confirming the cardiac hypertrophic effect. Moreover, NHE1 transgenic mice also showed increased collagen deposition, upregulation of CD44 and phosphorylation of p90 ribosomal s6 kinase (RSK), effects that were regressed in OPN knockout mice. In conclusion, we developed an interesting comparative model of active NHE1 transgenic mouse lines which express a dilated hypertrophic phenotype expressing CD44 and phosphorylated RSK, effects which were regressed in absence of OPN.
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Cardiomegalia/metabolismo , Osteopontina/metabolismo , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Intercambiador 1 de Sodio-Hidrógeno/metabolismo , Animales , Cardiomegalia/genética , Regulación de la Expresión Génica , Receptores de Hialuranos/genética , Receptores de Hialuranos/metabolismo , Ratones Noqueados , Ratones Transgénicos , Miocardio/metabolismo , Miocardio/patología , Miocitos Cardíacos/metabolismo , Osteopontina/genética , Fosforilación , Intercambiador 1 de Sodio-Hidrógeno/genéticaRESUMEN
p90 ribosomal S6 kinase (p90RSK) constitutes a family of serine/threonine kinases that have been shown to be involved in cell proliferation of various malignancies via direct or indirect effects on the cell-cycle machinery. We investigated the role of p90RSK in lung adenocarcinomas and whether the inhibition of p90RSK diminishes cancer progression. Moreover, we investigated the involvement of glycogen synthase kinase-3ß (GSK-3ß) and osteopontin (OPN) in the p90RSK-induced lung adenocarcinoma progression. p90RSK, OPN, and GSK-3ß protein expressions were examined in the A549 human lung adenocarcinoma cell line in the presence and absence of BI-D1870 (BID), a p90RSK inhibitor. Gene expression of anti-apoptotic and pro-apoptotic markers namely Bcl2 and Bax, respectively, were studied by reverse transcription polymerase chain reaction. In addition, the A549 lung adenocarcinoma cell line was characterized for cell proliferation using the MTT assay and cell migration using the scratch migration assay. Our study revealed that total RSK1 protein expression is over expressed in the A549 human lung adenocarcinoma cell line, an effect which is significantly reduced upon pretreatment with BID (69.32 ± 12.41 % of control; P < 0.05). The inhibition of p90RSK also showed a significant suppression of cell proliferation (54.3 ± 6.73 % of control; P < 0.01) and cell migration (187.90 ± 16.10 % of control; P < 0.01). Treatment of the A549 cells with BID regressed the expression of Bcl2 mRNA (56.92 ± 6.07 % of control; P < 0.01). BID also regressed protein expression of OPN (79.57 ± 5.32 % of control; P < 0.05) and phospho-GSK-3ß (73.04 ± 8.95 % of control; P < 0.05). The p90RSK has an essential role in promoting tumor growth and proliferation in non-small cell lung cancer (NSCLC). BID may serve as an alternative cancer treatment in NSCLC.
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Adenocarcinoma/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glucógeno Sintasa Quinasa 3 beta/biosíntesis , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas de Neoplasias/metabolismo , Osteopontina/biosíntesis , Pteridinas/farmacología , Proteínas Quinasas S6 Ribosómicas 90-kDa/antagonistas & inhibidores , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Glucógeno Sintasa Quinasa 3 beta/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Osteopontina/genética , Proteínas Quinasas S6 Ribosómicas 90-kDa/genética , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismoRESUMEN
A global survey of cancer has shown that lung cancer is the most common cause of the new cancer cases and cancer deaths in men worldwide. The mortality from lung cancer is more than the combined mortality from breast, prostate and colorectal cancers. The two major histological types of lung cancer are non-small cell lung cancer (NSCLC) accounting for about 85 % of cases and small cell lung cancer accounting for 15 % of cases. NSCLC, the more prevalent form of lung cancer, is often diagnosed at an advanced stage and has a very poor prognosis. Many factors have been shown to contribute to the development of lung cancer in humans including tobacco smoking, exposure to environmental carcinogens (asbestos, or radon) and genetic factors. Despite the advances in treatment, lung cancer remains one of the leading causes of cancer death worldwide. Interestingly, the overall 5 year survival from lung cancer has not changed appreciably in the past 25 years. For this reason, novel and more effective treatments and strategies for NSCLC are critically needed. p90 ribosomal S6 kinase (RSK), a serine threonine kinase that lies downstream of the Ras-MAPK (mitogen activated protein kinase) cascade, has been demonstrated to be involved in the regulation of cell proliferation in various malignancies through indirect (e.g., modulation of transcription factors) or direct effects on the cell-cycle machinery. Increased expression of RSK has been demonstrated in various cancers, including lung cancer. This review focuses on the role of RSK in lung cancer and its potential therapeutic application.
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Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/enzimología , Terapia Molecular Dirigida , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Animales , Apoptosis/efectos de los fármacos , Humanos , Neoplasias Pulmonares/patología , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Quinasas S6 Ribosómicas 90-kDa/químicaRESUMEN
Enhanced expression and activity of the Na+/H+ exchanger isoform 1 (NHE1) has been implicated in cardiomyocyte hypertrophy in various experimental models. The upregulation of NHE1 was correlated with an increase in osteopontin (OPN) expression in models of cardiac hypertrophy (CH), and the mechanism for this remains to be delineated. To determine whether the expression of active NHE1-induces OPN and contributes to the hypertrophic response in vitro, cardiomyocytes were infected with the active form of the NHE1 adenovirus or transfected with OPN silencing RNA (siRNA-OPN) and characterized for cardiomyocyte hypertrophy. Expression of NHE1 in cardiomyocytes resulted in a significant increase in cardiomyocyte hypertrophy markers: cell surface area, protein content, ANP mRNA and expression of phosphorylated-GATA4. NHE1 activity was also significantly increased in cardiomyocytes expressing active NHE1. Interestingly, transfection of cardiomyocytes with siRNA-OPN significantly abolished the NHE1-induced cardiomyocyte hypertrophy. siRNA-OPN also significantly reduced the activity of NHE1 in cardiomyocytes expressing NHE1 (68.5±0.24%; P<0.05), confirming the role of OPN in the NHE1-induced hypertrophic response. The hypertrophic response facilitated by NHE1-induced OPN occurred independent of the extracellular-signal-regulated kinases and Akt, but required p90-ribosomal S6 kinase (RSK). The ability of OPN to facilitate the NHE1-induced hypertrophic response identifies OPN as a potential therapeutic target to reverse the hypertrophic effect induced by the expression of active NHE1.
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Cardiomegalia/metabolismo , Miocitos Cardíacos/metabolismo , Osteopontina/metabolismo , Intercambiadores de Sodio-Hidrógeno/metabolismo , Animales , Cardiomegalia/genética , Cardiomegalia/patología , Aumento de la Célula , Células Cultivadas , Miocitos Cardíacos/patología , Osteopontina/genética , Fosforilación , ARN Interferente Pequeño , Ratas , Transducción de Señal/fisiología , Intercambiador 1 de Sodio-Hidrógeno , Intercambiadores de Sodio-Hidrógeno/genética , TransfecciónRESUMEN
Osteopontin (OPN), a multifunctional glycophosphoprotein, has been reported to contribute to the development and progression of cardiac remodeling and hypertrophy. Cardiac-specific OPN knockout mice were protected against hypertrophy and fibrosis mediated by Ang II. Recently, transgenic mice expressing the active form of the Na(+)/H(+) exchanger isoform 1 (NHE1) developed spontaneous hypertrophy in association with elevated levels of OPN. The mechanism by which active NHE1 induces OPN expression and contributes to the hypertrophic response remains unclear. To validate whether expression of the active form of NHE1 induces OPN, cardiomyocytes were stimulated with Ang II, a known inducer of both OPN and NHE1. Ang II induced hypertrophy and increased OPN protein expression (151.6 ± 28.19 %, P < 0.01) and NHE1 activity in H9c2 cardiomyoblasts. Ang II-induced hypertrophy and OPN protein expression were regressed in the presence of an NHE1 inhibitor, EMD 87580, or a calcineurin inhibitor, FK506. In addition, our results indicated that activation of NHE1-induced NFAT3 translocation into the nucleus and a significant activation of the transcription factor Gata4 (NHE1: 149 ± 28 % of control, P < 0.05). NHE1-induced activation of Gata4 was inhibited by FK506. In summary, our results suggest that activation of NHE1 induces hypertrophy through the activation of NFAT3/Gata4 and OPN expression.