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The COVID-19 pandemic reminded us of the urgent need for new antivirals to control emerging infectious diseases and potential future pandemics. Immunotherapy has revolutionized oncology and could complement the use of antivirals, but its application to infectious diseases remains largely unexplored. Nucleoside analogs are a class of agents widely used as antiviral and anti-neoplastic drugs. Their antiviral activity is generally based on interference with viral nucleic acid replication or transcription. Based on our previous work and computer modeling, we hypothesize that antiviral adenosine analogs, like remdesivir, have previously unrecognized immunomodulatory properties which contribute to their therapeutic activity. In the case of remdesivir, we here show that these properties are due to its metabolite, GS-441524, acting as an Adenosine A2A Receptor antagonist. Our findings support a new rationale for the design of next-generation antiviral agents with dual - immunomodulatory and intrinsic - antiviral properties. These compounds could represent game-changing therapies to control emerging viral diseases and future pandemics.
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Adenosina Monofosfato , Adenosina , Alanina , Antivirales , COVID-19 , SARS-CoV-2 , Antivirales/farmacología , Antivirales/química , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/inmunología , Adenosina/análogos & derivados , Adenosina/farmacología , Adenosina/química , Humanos , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/farmacología , Alanina/análogos & derivados , Alanina/farmacología , Alanina/química , COVID-19/inmunología , COVID-19/virología , Animales , Agentes Inmunomoduladores/farmacología , Agentes Inmunomoduladores/química , Antagonistas del Receptor de Adenosina A2/farmacología , Antagonistas del Receptor de Adenosina A2/química , Antagonistas del Receptor de Adenosina A2/uso terapéutico , Pandemias , Tratamiento Farmacológico de COVID-19 , Chlorocebus aethiops , Replicación Viral/efectos de los fármacos , Células Vero , Betacoronavirus/efectos de los fármacos , Betacoronavirus/inmunología , Receptor de Adenosina A2A/metabolismo , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virologíaRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) accounts for more than 90% of all pancreatic cancers and is the most fatal of all cancers. The treatment response from combination chemotherapies is far from satisfactory and surgery remains the mainstay of curative strategies. These challenges warrant identifying effective treatments for combating this deadly cancer. PDAC tumor progression is associated with the robust activation of the coagulation system. Notably, cancer-associated thrombosis (CAT) is a significant risk factor in PDAC. CAT is a concept whereby cancer cells promote thromboembolism, primarily venous thromboembolism (VTE). Of all cancer types, PDAC is associated with the highest risk of developing VTE. Hypoxia in a PDAC tumor microenvironment also elevates thrombotic risk. Direct oral anticoagulants (DOACs) or low-molecular-weight heparin (LMWH) are used only as thromboprophylaxis in PDAC. However, a precision medicine approach is recommended to determine the precise dose and duration of thromboprophylaxis in clinical setting.
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Neoplasias Pancreáticas , Tromboembolia Venosa , Humanos , Tromboembolia Venosa/etiología , Tromboembolia Venosa/prevención & control , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Anticoagulantes/uso terapéutico , Factores de Riesgo , Animales , Microambiente TumoralRESUMEN
Aggressive inflammatory response leading to hypercoagulability has been found to be associated with disease severity in COVID-19 patients and portends bad treatment outcome. A state of acute disseminated intravascular coagulation (DIC), along with pulmonary embolism and/or deep vein thrombosis, has been observed in critically ill ICU patients. Autopsy reports of COVID-19 patients demonstrated microthrombi in lungs and in other organs, as well as marked inflammatory changes, characteristic clinicopathological features that exacerbate disease severity. Vitamin D supplementation was recommended by many clinicians across the globe to improve clinical symptoms of COVID-19 patients, mainly because of its immunomodulatory roles on immune cells. Furthermore, vitamin D and its associated molecules are also known to directly or indirectly regulate various thrombotic pathways. We propose that vitamin D supplementation not only attenuates the risk of Acute Respiratory Disease Syndrome (ARDS) but it also may have a role in reducing coagulation abnormalities in critically ill COVID-19 patients. The overarching goal of this review is to discuss the effects of vitamin D on coagulation pathways and other intertwined processes leading to thrombosis. Many clinical trials are currently investigating the efficacy of vitamin D supplementation in reducing the risk of COVID-19 infection. However, randomized placebo control clinical trials are also necessary to ascertain the effect of vitamin D supplementation on reducing the risk of coagulopathy in COVID-19 patients.
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Tratamiento Farmacológico de COVID-19 , COVID-19/etiología , Vitamina D/farmacología , Vitamina D/fisiología , Trastornos de la Coagulación Sanguínea/virología , COVID-19/complicaciones , Humanos , Quiste del Uraco/etiología , Deficiencia de Vitamina D/virologíaRESUMEN
Neuron-glial related cell adhesion molecule NrCAM is a newly identified negative regulator of spine density that genetically interacts with Semaphorin3F (Sema3F), and is implicated in autism spectrum disorders (ASD). To investigate a role for NrCAM in spine pruning during the critical adolescent period when networks are established, we generated novel conditional, inducible NrCAM mutant mice (Nex1Cre-ERT2: NrCAMflox/flox). We demonstrate that NrCAM functions cell autonomously during adolescence in pyramidal neurons to restrict spine density in the visual (V1) and medial frontal cortex (MFC). Guided by molecular modeling, we found that NrCAM promoted clustering of the Sema3F holoreceptor complex by interfacing with Neuropilin-2 (Npn2) and PDZ scaffold protein SAP102. NrCAM-induced receptor clustering stimulated the Rap-GAP activity of PlexinA3 (PlexA3) within the holoreceptor complex, which in turn, inhibited Rap1-GTPase and inactivated adhesive ß1 integrins, essential for Sema3F-induced spine pruning. These results define a developmental function for NrCAM in Sema3F receptor signaling that limits dendritic spine density on cortical pyramidal neurons during adolescence.
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Moléculas de Adhesión Celular/fisiología , Espinas Dendríticas/fisiología , Lóbulo Frontal/crecimiento & desarrollo , Proteínas de la Membrana/fisiología , Proteínas del Tejido Nervioso/fisiología , Células Piramidales/fisiología , Corteza Visual/crecimiento & desarrollo , Animales , Guanilato-Quinasas/fisiología , Ratones Transgénicos , Modelos Moleculares , Transducción de SeñalRESUMEN
Selective modulation of specific benzodiazepine receptor (BzR) gamma amino butyric acid-A (GABA(A)) receptor ion channels has been identified as an important method for separating out the variety of pharmacological effects elicited by BzR-related drugs. Importantly, it has been demonstrated that both α2ß(2/3)γ2 (α2BzR) and α3BzR (and/or α2/α3) BzR subtype selective ligands exhibit anxiolytic effects with little or no sedation. Previously we have identified several such ligands; however, three of our parent ligands exhibited significant metabolic liability in rodents in the form of a labile ester group. Here eight analogs are reported which were designed to circumvent this liability by utilizing a rational replacement of the ester moiety based on medicinal chemistry precedents. In a metabolic stability study using human liver microsomes, four compounds were found to undergo slower metabolic transformation, as compared to their corresponding ester analogs. These compounds were also evaluated in in vitro efficacy assays. Additionally, bioisostere 11 was evaluated in a rodent model of anxiety. It exhibited anxiolytic activity at doses of 10 and 100mg/kg and was devoid of sedative properties.
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Ansiolíticos/química , Ansiolíticos/uso terapéutico , Benzodiazepinas/química , Benzodiazepinas/uso terapéutico , Microsomas Hepáticos/metabolismo , Receptores de GABA-A/metabolismo , Animales , Ansiolíticos/metabolismo , Ansiolíticos/farmacocinética , Ansiedad/tratamiento farmacológico , Benzodiazepinas/metabolismo , Benzodiazepinas/farmacocinética , Humanos , Ligandos , Locomoción/efectos de los fármacos , RatonesRESUMEN
BACKGROUND: The efficacy of CB-103 was evaluated in preclinical models of both ER+ and TNBC. Furthermore, the therapeutic efficacy of combining CB-103 with fulvestrant in ER+ BC and paclitaxel in TNBC was determined. METHODS: CB-103 was screened in combination with a panel of anti-neoplastic drugs. We evaluated the anti-tumor activity of CB-103 with fulvestrant in ESR1-mutant (Y537S), endocrine-resistant BC xenografts. In the same model, we examined anti-CSC activity in mammosphere formation assays for CB-103 alone or in combination with fulvestrant or palbociclib. We also evaluated the effect of CB-103 plus paclitaxel on primary tumors and CSC in a GSI-resistant TNBC model HCC1187. Comparisons between groups were performed with a two-sided unpaired Students' t-test. A one-way or two-way ANOVA followed by Tukey's post-analysis was performed to analyze the in vivo efficacy study results. THE RESULTS: CB-103 showed synergism with fulvestrant in ER+ cells and paclitaxel in TNBC cells. CB-103 combined with fulvestrant or paclitaxel potently inhibited mammosphere formation in both models. Combination of CB-103 and fulvestrant significantly reduced tumor volume in an ESR1-mutant, the endocrine-resistant BC model. In a GSI-resistant TNBC model, CB-103 plus paclitaxel significantly delayed tumor growth compared to paclitaxel alone. CONCLUSION: our data indicate that CB-103 is an attractive candidate for clinical investigation in endocrine-resistant, recurrent breast cancers with biomarker-confirmed Notch activity in combination with SERDs and/or CDKis and in TNBCs with biomarker-confirmed Notch activity in combination with taxane-containing chemotherapy regimens.
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Introduction: Triple-negative breast cancer (TNBC) comprises a heterogeneous group of clinically aggressive tumors with high risk of recurrence and metastasis. Current pharmacological treatment options remain largely limited to chemotherapy. Despite promising results, the efficacy of immunotherapy and chemo-immunotherapy in TNBC remains limited. There is strong evidence supporting the involvement of Notch signaling in TNBC progression. Expression of Notch1 and its ligand Jagged1 correlate with poor prognosis. Notch inhibitors, including g-secretase inhibitors (GSIs), are quite effective in preclinical models of TNBC. However, the success of GSIs in clinical trials has been limited by their intestinal toxicity and potential for adverse immunological effects, since Notch plays key roles in T-cell activation, including CD8 T-cells in tumors. Our overarching goal is to replace GSIs with agents that lack their systemic toxicity and ideally, do not affect tumor immunity. We identified sulindac sulfide (SS), the active metabolite of FDA-approved NSAID sulindac, as a potential candidate to replace GSIs. Methods: We investigated the pharmacological and immunotherapeutic properties of SS in TNBC models in vitro, ex-vivo and in vivo. Results: We confirmed that SS, a known γ-secretase modulator (GSM), inhibits Notch1 cleavage in TNBC cells. SS significantly inhibited mammosphere growth in all human and murine TNBC models tested. In a transplantable mouse TNBC tumor model (C0321), SS had remarkable single-agent anti-tumor activity and eliminated Notch1 protein expression in tumors. Importantly, SS did not inhibit Notch cleavage in T- cells, and the anti-tumor effects of SS were significantly enhanced when combined with a-PD1 immunotherapy in our TNBC organoids and in vivo. Discussion: Our data support further investigation of SS for the treatment of TNBC, in conjunction with chemo- or -chemo-immunotherapy. Repurposing an FDA-approved, safe agent for the treatment of TNBC may be a cost-effective, rapidly deployable therapeutic option for a patient population in need of more effective therapies.
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Sulindac , Neoplasias de la Mama Triple Negativas , Humanos , Animales , Ratones , Sulindac/farmacología , Sulindac/uso terapéutico , Secretasas de la Proteína Precursora del Amiloide , Neoplasias de la Mama Triple Negativas/metabolismo , Antiinflamatorios no Esteroideos/uso terapéutico , Modelos Animales de EnfermedadRESUMEN
PRECLINICAL STUDIES: have demonstrated a complex cross-talk between Notch and estrogen signaling in ERα-positive breast cancer. Gamma-secretase inhibitors (GSIs) are investigational agents that block the cleavage and activation of Notch receptors. In animal models of endocrine-resistant breast cancer, combinations of tamoxifen and GSIs produce additive or synergistic efficacy, while decreasing the intestinal toxicity of GSIs. However, results of a clinical trial of a GSI-endocrine therapy combination in the metastatic setting have not been published to date, nor had the safety of such combinations been investigated with longer term treatment. We conducted a phase 1b dose escalation trial (NCT01149356) of GSI RO4929097 with exemestane in patients with ERα+, metastatic breast cancer (MBC) STUDY OBJECTIVES: To determine the safety, tolerability and maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of RO4929097 when administered in combination with exemestane in patients with estrogen receptor positive metastatic breast cancer RESULTS: We enrolled 15 patients with MBC. Of 14 evaluable patients, one had a partial response, 6 had stable disease and 7 progressive disease. Twenty % of patients had stable disease for ≥ 6 months. Common toxicities included nausea (73.3%), anorexia (60%), hyperglycemia (53.3%), hypophosphatemia (46.7%), fatigue (66.7%) and cough (33.0%). Grade 3 toxicities were uncommon, and included hypophosphatemia (13%) and rash (6.3%). Rash was the only DLT observed at 140 mg/d. Results suggest a possible recommended phase 2 dose of 90 mg/d. Ten patients with evaluable archival tissue showed expression of PKCα, which correlated with expression of Notch4. Mammospheres from a PKCα-expressing, endocrine-resistant T47D cell line were inhibited by a GSI-fulvestrant combination CONCLUSIONS: Our data indicate that combinations including endocrine therapy and Notch inhibitors deserve further investigation in endocrine-resistant ERα-positive breast cancer.
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Androstadienos/uso terapéutico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzazepinas/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Fluorocarburos/uso terapéutico , Anciano , Neoplasias de la Mama/patología , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Dosis Máxima Tolerada , Persona de Mediana Edad , Metástasis de la Neoplasia , Receptor Notch3 , Receptores Notch/uso terapéuticoRESUMEN
A critical feature of cancer is the ability to induce immunosuppression and evade immune responses. Tumor-induced immunosuppression diminishes the effectiveness of endogenous immune responses and decreases the efficacy of cancer immunotherapy. In this study, we describe a new immunosuppressive pathway in which adenosine promotes Casitas B-lineage lymphoma b (Cbl-b)-mediated Notch1 degradation, causing suppression of CD8+ T-cells effector functions. Genetic knockout and pharmacological inhibition of Cbl-b prevents Notch1 degradation in response to adenosine and reactivates its signaling. Reactivation of Notch1 results in enhanced CD8+ T-cell effector functions, anti-cancer response and resistance to immunosuppression. Our work provides evidence that targeting the Cbl-b-Notch1 axis is a novel promising strategy for cancer immunotherapy.
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Linfoma , Neoplasias , Adenosina , Linfocitos T CD8-positivos , Humanos , Inmunoterapia , Receptor Notch1/genética , Receptor Notch1/metabolismoRESUMEN
Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer associated with a high recurrence and metastasis rate that affects African-American women disproportionately. The recent approval of targeted therapies for small subgroups of TNBC patients by the US 'Food and Drug Administration' is a promising development. The advancement of next-generation sequencing, particularly somatic exome panels, has raised hopes for more individualized treatment plans. However, the use of precision medicine for TNBC is a work in progress. This review will discuss the potential benefits and challenges of precision medicine for TNBC. A recent clinical trial designed to target TNBC patients based on their subtype-specific classification shows promise. Yet, tumor heterogeneity and sub-clonal evolution in primary and metastatic TNBC remain a challenge for oncologists to design adaptive precision medicine-based treatment plans.
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Triple-negative breast cancer (TNBC) is an aggressive, molecularly heterogeneous subtype of breast cancer. Obesity is associated with increased incidence and worse prognosis in TNBC through various potential mechanisms. Recent evidence suggests that the gut microbiome plays a central role in the progression of cancer, and that imbalances or dysbiosis in the population of commensal microbiota can lead to inflammation and contribute to tumor progression. Obesity is characterized by low-grade inflammation, and gut dysbiosis is associated with obesity, chronic inflammation, and failure of cancer immunotherapy. However, the debate on what constitutes a "healthy" gut microbiome is ongoing, and the connection among the gut microbiome, obesity, and TNBC has not yet been addressed. This study aims to characterize the role of obesity in modulating the gut microbiome in a syngeneic mouse model of TNBC. 16S rRNA sequencing and metagenomic analyses were performed to analyze and annotate genus and taxonomic profiles. Our results suggest that obesity decreases alpha diversity in the gut microbiome. Metagenomic analysis revealed that obesity was the only significant factor explaining the similarity of the bacterial communities according to their taxonomic profiles. In contrast to the analysis of taxonomic profiles, the analysis of variation of functional profiles suggested that obesity status, tumor presence, and the obesity-tumor interaction were significant in explaining the variation of profiles, with obesity having the strongest correlation. The presence of tumor modified the profiles to a greater extent in obese than in lean animals. Further research is warranted to understand the impact of the gut microbiome on TNBC progression and immunotherapy.
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Microbioma Gastrointestinal , Obesidad/complicaciones , Obesidad/microbiología , Neoplasias de la Mama Triple Negativas/complicaciones , Neoplasias de la Mama Triple Negativas/microbiología , Análisis de Varianza , Animales , Bacterias/genética , Microbioma Gastrointestinal/genética , Metagenómica , Ratones , Filogenia , ARN Ribosómico 16S/genética , Análisis de Secuencia de ARNRESUMEN
Notch signalling is involved in many aspects of cancer biology, including angiogenesis, tumour immunity and the maintenance of cancer stem-like cells. In addition, Notch can function as an oncogene and a tumour suppressor in different cancers and in different cell populations within the same tumour. Despite promising preclinical results and early-phase clinical trials, the goal of developing safe, effective, tumour-selective Notch-targeting agents for clinical use remains elusive. However, our continually improving understanding of Notch signalling in specific cancers, individual cancer cases and different cell populations, as well as crosstalk between pathways, is aiding the discovery and development of novel investigational Notch-targeted therapeutics.
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Antineoplásicos/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Neoplasias/metabolismo , Receptores Notch/metabolismo , Animales , Antineoplásicos/administración & dosificación , Sistemas de Liberación de Medicamentos/tendencias , Humanos , Inmunoterapia/métodos , Inmunoterapia/tendencias , Neoplasias/inmunología , Neoplasias/terapia , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/inmunología , Células Madre Neoplásicas/metabolismo , Receptores Notch/inmunología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
A series of 3,6-disubstituted ß-carbolines was synthesized and evaluated for their in vitro affinities at α(x)ß(3)γ(2) GABA(A)/benzodiazepine receptor subtypes by radioligand binding assays in search of α(1) subtype selective ligands to treat alcohol abuse. Analogues of ß-carboline-3-carboxylate-t-butyl ester (ßCCt, 1) were synthesized via a CDI-mediated process and the related 6-substituted ß-carboline-3-carboxylates 6 including WYS8 (7) were synthesized via a Sonogashira or Stille coupling processes from 6-iodo-ßCCt (5). The bivalent ligands of ßCCt (32 and 33) were also designed and prepared via a palladium-catalyzed homocoupling process to expand the structure-activity relationships (SAR) to larger ligands. Based on the pharmacophore/receptor model, a preliminary SAR study on 34 analogues illustrated that large substituents at position-6 of the ß-carbolines were well tolerated. As expected, these groups are proposed to project into the extracellular domain (L(Di) region) of GABA(A)/Bz receptors (see 32 and 33). Moreover, substituents located at position-3 of the ß-carboline nucleus exhibited a conserved stereo interaction in lipophilic pocket L(1), while N(2) presumably underwent a hydrogen bonding interaction with H(1). Three novel ß-carboline ligands (ßCCt, 3PBC and WYS8), which preferentially bound to α1 BzR subtypes permitted a comparison of the pharmacological efficacies with a range of classical BzR antagonists (flumazenil, ZK93426) from several different structural groups and indicated these ß-carbolines were 'near GABA neutral antagonists'. Based on the SAR, the most potent (in vitro) α(1) selective ligand was the 6-substituted acetylenyl ßCCt (WYS8, 7). Earlier both ßCCt and 3PBC had been shown to reduce alcohol self-administration in alcohol preferring (P) and high alcohol drinking (HAD) rats but had little or no effect on sucrose self-administration.(1-3) Moreover, these two ß-carbolines were orally active, and in addition, were anxiolytic in P rats but were only weakly anxiolytic in rodents. These data prompted the synthesis of the ß-carbolines presented here.
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Alcoholismo/tratamiento farmacológico , Benzodiazepinas/química , Carbolinas/química , Antagonistas de Receptores de GABA-A/síntesis química , Receptores de GABA-A/química , Animales , Sitios de Unión , Carbolinas/síntesis química , Carbolinas/uso terapéutico , Línea Celular , Simulación por Computador , Antagonistas de Receptores de GABA-A/química , Antagonistas de Receptores de GABA-A/uso terapéutico , Humanos , Subunidades de Proteína/antagonistas & inhibidores , Subunidades de Proteína/metabolismo , Ratas , Receptores de GABA-A/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The COVID-19 pandemic has caused monumental mortality, and there are still no adequate therapies. Most severely ill COVID-19 patients manifest a hyperactivated immune response, instigated by interleukin 6 (IL6) that triggers a so called "cytokine storm" and coagulopathy. Hypoxia is also associated with COVID-19. So far overlooked is the fact that both IL6 and hypoxia depress the abundance of a key anticoagulant, Protein S. We speculate that the IL6-driven cytokine explosion plus hypoxemia causes a severe drop in Protein S level that exacerbates the thrombotic risk in COVID-19 patients. Here we highlight a mechanism by which the IL6-hypoxia curse causes a deadly hypercoagulable state in COVID-19 patients, and we suggest a path to therapy.
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Infecciones por Coronavirus , Síndrome de Liberación de Citoquinas , Hipoxia , Pandemias , Neumonía Viral , Proteína S , Trombofilia/inmunología , Enzima Convertidora de Angiotensina 2 , Anticoagulantes/metabolismo , Anticoagulantes/farmacología , Betacoronavirus/fisiología , COVID-19 , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/terapia , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/virología , Manejo de la Enfermedad , Humanos , Hipoxia/sangre , Hipoxia/etiología , Hipoxia/inmunología , Interleucina-6/sangre , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/sangre , Neumonía Viral/inmunología , Neumonía Viral/terapia , Proteína S/metabolismo , Proteína S/farmacología , SARS-CoV-2 , Índice de Severidad de la EnfermedadRESUMEN
In recent years, the need for a low-cost emergency ventilation system has increased unprecedentedly. Mechanical ventilation systems are widely used to cater to sudden oxygen demands, low breathing rates, and critical conditions during bradycardia and tachycardia. In this research, a new design of mechanical ventilation system synced with the tidal volume requirements of the patient using a piezoelectric belt has been proposed. The device proposed has various modes of ventilation-ACV (assisted controlled ventilation), SIMV (synchronized intermittent mandatory ventilation), and NIV (non-invasive ventilation), depending on the patient's requirements. A digital interface or user-friendly software has also been developed to help medical professionals easily monitor a patient's medical conditions. Finally, the automation that controls the ventilation mechanism of the device has been tested and validated with a conventional ventilator, and it has been found that the accuracy of the device in terms of delivering the exact quantity of air into the patient according to his requirements has been improved significantly. Further, the comparative study of the experimental data indicated that 5-10% error in detecting inhale and exhale attempt of a patient was detected with the conventional ventilator.
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COVID-19 , Regulación hacia Abajo , Proteína S , SARS-CoV-2 , Trombosis , Humanos , COVID-19/complicaciones , COVID-19/sangre , COVID-19/virología , Proteína S/metabolismo , Masculino , Femenino , Trombosis/sangre , Persona de Mediana Edad , AncianoRESUMEN
The stable conformations of GABA(A)-benzodiazepine receptor bivalent ligands were determined by low temperature NMR spectroscopy and confirmed by single crystal X-ray analysis. The stable conformations in solution correlated well with those in the solid state. The linear conformation was important for these dimers to access the binding site and exhibit potent in vitro affinity and was illustrated for alpha5 subtype selective ligands. Bivalent ligands with an oxygen-containing linker folded back upon themselves both in solution and the solid state. Dimers which are folded do not bind to Bz receptors.
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Benzodiazepinas , Receptores de GABA-A , Benzodiazepinas/química , Benzodiazepinas/metabolismo , Sitios de Unión , Frío , Cristalografía por Rayos X , Dimerización , Ligandos , Espectroscopía de Resonancia Magnética , Conformación Molecular , Oxígeno/química , Oxígeno/metabolismo , Receptores de GABA-A/química , Receptores de GABA-A/metabolismo , Relación Estructura-ActividadRESUMEN
Cancer immunotherapy, which stimulates or augments host immune responses to treat malignancies, is the latest development in the rapidly advancing field of cancer immunology. The basic principles of immunotherapies are either to enhance the functions of specific components of the immune system or to neutralize immune-suppressive signals produced by cancer cells or tumor microenvironment cells. When successful, these approaches translate into long-term survival for patients. However, durable responses are only seen in a subset of patients and so far, only in some cancer types. As for other cancer treatments, resistance to immunotherapy can also develop. Numerous research groups are trying to understand why immunotherapy is effective in some patients but not others and to develop strategies to enhance the effectiveness of immunotherapy. The Notch signaling pathway is involved in many aspects of tumor biology, from angiogenesis to cancer stem cell maintenance to tumor immunity. The role of Notch in the development and modulation of the immune response is complex, involving an intricate crosstalk between antigen-presenting cells, T-cell subpopulations, cancer cells, and other components of the tumor microenvironment. Elegant studies have shown that Notch is a central mediator of tumor-induced T-cell anergy and that activation of Notch1 in CD8 T-cells enhances cancer immunotherapy. Tumor-infiltrating myeloid cells, including myeloid-derived suppressor cells, altered dendritic cells, and tumor-associated macrophages along with regulatory T cells, are major obstacles to the development of successful cancer immunotherapies. In this article, we focus on the roles of Notch signaling in modulating tumor-infiltrating myeloid cells and discuss implications for therapeutic strategies that modulate Notch signaling to enhance cancer immunotherapy.
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Inmunomodulación , Células Mieloides/inmunología , Células Mieloides/metabolismo , Neoplasias/inmunología , Neoplasias/metabolismo , Receptores Notch/metabolismo , Transducción de Señal , Animales , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Humanos , Inmunoterapia , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Neoplasias/patología , Neoplasias/terapia , Microambiente Tumoral/inmunologíaRESUMEN
Advanced prostate cancer invariably recurs despite androgen deprivation therapy. The androgen receptor (AR) likely plays a key role in this progression and in the continued survival and proliferation of prostate cancer cells in the low androgen environment. Cross-talk with growth factor receptors, such as epidermal growth factor receptor (EGFR) family, has been postulated as a potential mechanism to activate AR in recurrent prostate cancer. We have investigated the role of HER-2/neu (ErbB-2) tyrosine kinase in AR function by characterizing the effect of inhibiting endogenous HER-2 activity in LNCaP cells. We used two independent methods, expression of intracellular single-chain antibody against HER-2 and treatment with a novel dual EGFR/HER-2 kinase inhibitor GW572016 (lapatinib). Expression of intracellular HER-2 antibody scFv-5R and treatment with GW572016 inhibited HER-2 signaling. This HER-2 inhibition led to impairment of AR-mediated functions, such as androgen-stimulated growth and the induction of endogenous prostate-specific antigen (PSA) mRNA and protein. Androgen-stimulated recruitment of AR and histone acetylation at the androgen responsive enhancer of the PSA gene, detected by chromatin immunoprecipitation analysis, were impaired by HER-2 inhibition. GW572016 was more potent in its ability to inhibit PSA expression and AR recruitment and histone acetylation than the EGFR-selective kinase inhibitor ZD1839 (gefitinib), consistent with the HER-2 kinase playing the major role in AR regulation. These results show that HER-2 signaling is required for optimal transcriptional activity of AR in prostate cancer cells and suggest that HER-2 inhibition may provide a novel strategy to disrupt AR function in prostate cancer.
Asunto(s)
Antagonistas de Receptores Androgénicos , Neoplasias de la Próstata/metabolismo , Receptor ErbB-2/antagonistas & inhibidores , Acetilación/efectos de los fármacos , Andrógenos/fisiología , Línea Celular Tumoral , Cromatina/efectos de los fármacos , Cromatina/genética , Inmunoprecipitación de Cromatina , Dihidrotestosterona/farmacología , Receptores ErbB/antagonistas & inhibidores , Gefitinib , Histonas/metabolismo , Humanos , Fragmentos de Inmunoglobulinas/biosíntesis , Fragmentos de Inmunoglobulinas/genética , Fragmentos de Inmunoglobulinas/inmunología , Lapatinib , Masculino , Antígeno Prostático Específico/antagonistas & inhibidores , Antígeno Prostático Específico/biosíntesis , Antígeno Prostático Específico/genética , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/enzimología , Neoplasias de la Próstata/genética , Quinazolinas/farmacología , Receptor ErbB-2/inmunología , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Receptores Androgénicos/fisiología , Elementos de Respuesta , Transcripción Genética/efectos de los fármacos , Transcripción Genética/fisiologíaRESUMEN
Over the last years, genetic studies have greatly improved our knowledge on the receptor subtypes mediating various pharmacological effects of positive allosteric modulators at GABA(A) receptors. This stimulated the development of new benzodiazepine (BZ)-like ligands, especially those inactive/low-active at GABA(A) receptors containing the alpha(1) subunit, with the aim of generating more selective drugs. Hereby, the affinity and efficacy of four recently synthesized BZ site ligands: SH-053-2'N, SH-053-S-CH3-2'F, SH-053-R-CH3-2'F and JY-XHe-053 were assessed. They were also studied in behavioral tests of spontaneous locomotor activity, elevated plus maze, and water maze in rats, which are considered predictive of, respectively, the sedative, anxiolytic, and amnesic influence of BZs. The novel ligands had moderately low to low affinity and mild to partial agonistic efficacy at GABA(A) receptors containing the alpha(1) subunit, with variable, but more pronounced efficacy at other BZ-sensitive binding sites. While presumably alpha(1) receptor-mediated sedative effects of GABA(A) modulation were not fully eliminated with any of the ligands tested, only SH-053-2'N and SH-053-S-CH3-2'F, both dosed at 30 mg/kg, exerted anxiolytic effects. The lack of clear anxiolytic-like activity of JY-XHe-053, despite its efficacy at alpha(2)- and alpha(3)-GABA(A) receptors, may have been partly connected with its preferential affinity at alpha(5)-GABA(A) receptors coupled with weak agonist activity at alpha(1)-containing subtypes. The memory impairment in water-maze experiments, generally reported with BZ site agonists, was completely circumvented with all four ligands. The results suggest that a substantial amount of activity at alpha(1) GABA(A) receptors is needed for affecting spatial learning and memory impairments, while much weaker activity at alpha(1)- and alpha(5)-GABA(A) receptors is sufficient for eliciting sedation.