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1.
Nat Commun ; 11(1): 4931, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-33004795

RESUMEN

Testis-restricted melanoma antigen (MAGE) proteins are frequently hijacked in cancer and play a critical role in tumorigenesis. MAGEs assemble with E3 ubiquitin ligases and function as substrate adaptors that direct the ubiquitination of novel targets, including key tumor suppressors. However, how MAGEs recognize their targets is unknown and has impeded the development of MAGE-directed therapeutics. Here, we report the structural basis for substrate recognition by MAGE ubiquitin ligases. Biochemical analysis of the degron motif recognized by MAGE-A11 and the crystal structure of MAGE-A11 bound to the PCF11 substrate uncovered a conserved substrate binding cleft (SBC) in MAGEs. Mutation of the SBC disrupted substrate recognition by MAGEs and blocked MAGE-A11 oncogenic activity. A chemical screen for inhibitors of MAGE-A11:substrate interaction identified 4-Aminoquinolines as potent inhibitors of MAGE-A11 that show selective cytotoxicity. These findings provide important insights into the large family of MAGE ubiquitin ligases and identify approaches for developing cancer-specific therapeutics.


Asunto(s)
Antígenos de Neoplasias/ultraestructura , Proteínas de Neoplasias/ultraestructura , Neoplasias/tratamiento farmacológico , Ubiquitina-Proteína Ligasas/metabolismo , Factores de Escisión y Poliadenilación de ARNm/metabolismo , Secuencias de Aminoácidos , Aminoquinolinas/farmacología , Aminoquinolinas/uso terapéutico , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carcinogénesis/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HEK293 , Células HeLa , Ensayos Analíticos de Alto Rendimiento , Humanos , Mutagénesis , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/patología , Prueba de Estudio Conceptual , Unión Proteica/efectos de los fármacos , Unión Proteica/genética , Dominios Proteicos/genética , Mapeo de Interacción de Proteínas , Relación Estructura-Actividad , Especificidad por Sustrato/efectos de los fármacos , Especificidad por Sustrato/genética , Ubiquitinación/efectos de los fármacos , Ubiquitinación/genética
3.
Nat Commun ; 11(1): 4965, 2020 10 02.
Artículo en Inglés | MEDLINE | ID: mdl-33009371

RESUMEN

Next-generation sequencing (NGS) can identify novel cancer targets. However, interpreting the molecular findings and accessing drugs/clinical trials is challenging. Furthermore, many tumors show resistance to monotherapies. To implement a precision strategy, we initiated a multidisciplinary (basic/translational/clinical investigators, bioinformaticians, geneticists, and physicians from multiple specialties) molecular tumor board (MTB), which included a project manager to facilitate obtaining clinical-grade biomarkers (blood/tissue NGS, specific immunohistochemistry/RNA expression including for immune-biomarkers, per physician discretion) and medication-acquisition specialists/clinical trial coordinators/navigators to assist with medication access. The MTB comprehensively reviewed patient characteristics to develop N-of-One treatments implemented by the treating physician's direction under the auspices of a master protocol. Overall, 265/429 therapy-evaluable patients (62%) were matched to ≥1 recommended drug. Eighty-six patients (20%) matched to all drugs recommended by MTB, including combinatorial approaches, while 38% received physician's choice regimen, generally with unmatched approach/low degree of matching. Our results show that patients who receive MTB-recommended regimens (versus physician choice) have significantly longer progression-free (PFS) and overall survival (OS), and are better matched to therapy. High (≥50%) versus low (<50%) Matching Score therapy (roughly reflecting therapy matched to ≥50% versus <50% of alterations) independently correlates with longer PFS (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.50-0.80; P < 0.001) and OS (HR, 0.67; 95% CI, 0.50-0.90; P = 0.007) and higher stable disease ≥6 months/partial/complete remission rate (52.1% versus 30.4% P < 0.001) (all multivariate). In conclusion, patients who receive MTB-based therapy are better matched to their genomic alterations, and the degree of matching is an independent predictor of improved oncologic outcomes including survival.


Asunto(s)
Neoplasias/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Niño , Preescolar , ADN Tumoral Circulante/genética , Supervivencia sin Enfermedad , Femenino , Genoma Humano , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Medicina de Precisión , Resultado del Tratamiento , Adulto Joven
4.
Oncol Nurs Forum ; 47(6): 629-630, 2020 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-33063785

RESUMEN

Infusion of antineoplastic medications in nontraditional settings, including the home, is not a new concept. However, the emergence of the novel coronavirus, COVID-19, has accelerated conversations around ensuring that patients with cancer can continue timely cancer treatment regimens while minimizing their risk of COVID-19 exposure and infection. Administration of antineoplastics through home infusion has been offered as a potential solution and continues to gain momentum among healthcare facilities and third-party payers.


Asunto(s)
Antineoplásicos/administración & dosificación , Terapia de Infusión a Domicilio/enfermería , Neoplasias/tratamiento farmacológico , Infecciones por Coronavirus/epidemiología , Humanos , Enfermería Oncológica , Pandemias , Neumonía Viral/epidemiología , Riesgo , Sociedades de Enfermería , Estados Unidos/epidemiología
5.
BMC Bioinformatics ; 21(Suppl 14): 364, 2020 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-32998700

RESUMEN

BACKGROUND: Machine learning has been utilized to predict cancer drug response from multi-omics data generated from sensitivities of cancer cell lines to different therapeutic compounds. Here, we build machine learning models using gene expression data from patients' primary tumor tissues to predict whether a patient will respond positively or negatively to two chemotherapeutics: 5-Fluorouracil and Gemcitabine. RESULTS: We focused on 5-Fluorouracil and Gemcitabine because based on our exclusion criteria, they provide the largest numbers of patients within TCGA. Normalized gene expression data were clustered and used as the input features for the study. We used matching clinical trial data to ascertain the response of these patients via multiple classification methods. Multiple clustering and classification methods were compared for prediction accuracy of drug response. Clara and random forest were found to be the best clustering and classification methods, respectively. The results show our models predict with up to 86% accuracy; despite the study's limitation of sample size. We also found the genes most informative for predicting drug response were enriched in well-known cancer signaling pathways and highlighted their potential significance in chemotherapy prognosis. CONCLUSIONS: Primary tumor gene expression is a good predictor of cancer drug response. Investment in larger datasets containing both patient gene expression and drug response is needed to support future work of machine learning models. Ultimately, such predictive models may aid oncologists with making critical treatment decisions.


Asunto(s)
Antineoplásicos/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Aprendizaje Automático , Antineoplásicos/uso terapéutico , Área Bajo la Curva , Análisis por Conglomerados , Bases de Datos Genéticas , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Fluorouracilo/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico , Curva ROC
6.
Yakugaku Zasshi ; 140(10): 1243-1249, 2020.
Artículo en Japonés | MEDLINE | ID: mdl-32999203

RESUMEN

Here the author describes the tumor-selective delivery of a fluorescence photosensitizing agent and an antitumor agent, based on the polymer effect of an N-(2-hydroxypropyl)methacrylamide (HPMA) based copolymer, by utilizing the enhanced permeability and retention (EPR) effect seen in solid tumors. Firstly, the tumor distribution of the photosensitizer, zinc-protoporphyrin IX (ZnPP), was significantly increased by conjugation with the HPMA polymer (P-ZnPP). The P-ZnPP suppressed tumor growth by local generation of cytotoxic singlet oxygen, and the tumor tissue was visualized by fluorescence upon light irradiation. Subsequently, a two-step mechanism for tumor selectivity was observed for the cytotoxic anthracycline, pirarubicin (THP), which conjugated the HPMA-based copolymer via a hydrazone bond (P-THP). The EPR-dependent accumulation of P-THP and the tumor-selective release of THP in the tumor tissues led to highly tumor-selective toxicity. Rapid cell uptake of THP compared to other anthracyclines, and deeper P-THP penetration of the tumor cell spheroid were attributed to the superior antitumor activity of P-THP. The molecular weight of P-THP affected its antitumor activity; oligomeric P-THP derivatives with higher molecular weights, DP-THP and SP-THP, showed even higher antitumor activity. P-THP was effective for both implanted tumor and autochthonous tumor models. These results indicate that nano-sized anticancer drugs based on polymer effect are promising clinical therapeutics.


Asunto(s)
Antineoplásicos , Sistemas de Liberación de Medicamentos , Desarrollo de Medicamentos/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Fármacos Fotosensibilizantes , Polímeros , Protoporfirinas , Animales , Antraciclinas/química , Antraciclinas/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Doxorrubicina/análogos & derivados , Doxorrubicina/química , Doxorrubicina/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Metacrilatos/química , Terapia Molecular Dirigida , Peso Molecular , Neoplasias/patología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/metabolismo , Protoporfirinas/química , Protoporfirinas/metabolismo
7.
Molecules ; 25(19)2020 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-33050063

RESUMEN

The major groups of antioxidant compounds (isoflavonoids, xanthones, hydroxycinnamic acids) in the rhizome methanol extracts of four Ukrainian Iris sp. (Iris pallida, Iris hungarica, Iris sibirica, and Iris variegata) were qualitatively and quantitatively analyzed using HPLC-DAD and UPLC-MS/MS. Gallic acid, caffeic acid, mangiferin, tectoridin, irigenin, iristectorigenin B, irisolidone, 5,6-dihydroxy-7,8,3',5'-tetramethoxyisoflavone, irisolidone-7-O-ß-d-glucopyranoside, germanaism B, and nigricin were recognized by comparing their UV/MS spectra, chromatographic retention time (tR) with those of standard reference compounds. I. hungarica and I. variegata showed the highest total amount of phenolic compounds. Germanaism B was the most abundant component in the rhizomes of I. variegata (7.089 ± 0.032 mg/g) and I. hungarica (6.285 ± 0.030 mg/g). The compound analyses showed good calibration curve linearity (r2 > 0.999) and low detection and quantifications limit. These results validated the method for its use in the simultaneous quantitative evaluation of phenolic compounds in the studied Iris sp. I. hungarica and I. variegata rhizomes exhibited antioxidant activity, as demonstrated by the HPLC-ABTS system and NRF2 expression assay and anti-inflammatory activity on respiratory burst in human neutrophils. Moreover, the extracts showed anti-allergic and cytotoxic effects against cancer cells. Anti-coronavirus 229E and lipid formation activities were also evaluated. In summary, potent antioxidant marker compounds were identified in the examined Iris sp.


Asunto(s)
Antiinflamatorios/farmacología , Antineoplásicos/farmacología , Antioxidantes/farmacología , Antivirales/farmacología , Iris (Planta)/química , Extractos Vegetales/farmacología , Coronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/virología , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Células Tumorales Cultivadas
8.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 2447-2450, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-33018501

RESUMEN

The application of nanomedicine for diagnosis and treatment of cancer has immense potential, but has witnessed only limited clinical success, in part due to insufficient understanding of the role of nanomaterial properties and physiological variables in governing nanoparticle (NP) pharmacology. Here, we present a multiscale mathematical model to examine the effects of physiological changes associated with patient age on the pharmacokinetics and tumor delivery efficiency of NPs. We show that physiological changes due to aging prolong the residence of NPs in the systemic circulation, thereby improving passive accumulation of NPs in tumors.Clinical Relevance - Understanding the effect of inter-individual variability on the pharmacological behavior of nanomaterials will improve their clinical translatability.


Asunto(s)
Nanopartículas , Nanoestructuras , Neoplasias , Envejecimiento , Humanos , Nanomedicina , Neoplasias/tratamiento farmacológico
9.
Nat Commun ; 11(1): 5060, 2020 10 08.
Artículo en Inglés | MEDLINE | ID: mdl-33033246

RESUMEN

Fusion oncogenes (FOs) are common in many cancer types and are powerful drivers of tumor development. Because their expression is exclusive to cancer cells and their elimination induces cell apoptosis in FO-driven cancers, FOs are attractive therapeutic targets. However, specifically targeting the resulting chimeric products is challenging. Based on CRISPR/Cas9 technology, here we devise a simple, efficient and non-patient-specific gene-editing strategy through targeting of two introns of the genes involved in the rearrangement, allowing for robust disruption of the FO specifically in cancer cells. As a proof-of-concept of its potential, we demonstrate the efficacy of intron-based targeting of transcription factors or tyrosine kinase FOs in reducing tumor burden/mortality in in vivo models. The FO targeting approach presented here might open new horizons for the selective elimination of cancer cells.


Asunto(s)
Sistemas CRISPR-Cas/genética , Neoplasias/genética , Fusión de Oncogenes/genética , Animales , Secuencia de Bases , Línea Celular Tumoral , Proliferación Celular/genética , Doxorrubicina/uso terapéutico , Proteínas de Fusión bcr-abl/genética , Eliminación de Gen , Sitios Genéticos , Inestabilidad Genómica , Células HEK293 , Humanos , Intrones/genética , Ratones Desnudos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Proteínas de Fusión Oncogénica/genética , ARN Guia/metabolismo , Reproducibilidad de los Resultados , Ensayos Antitumor por Modelo de Xenoinjerto
11.
Lancet Oncol ; 21(10): e488-e494, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-33002444

RESUMEN

Patient-reported outcome (PRO) measures describe how a patient feels or functions and are increasingly being used in benefit-risk assessments in the development of cancer drugs. However, PRO research objectives are often ill-defined in clinical cancer trials, which can lead to misleading conclusions about patient experiences. The estimand framework is a structured approach to aligning a clinical trial objective with the study design, including endpoints and analysis. The estimand framework uses a multidisciplinary approach and can improve design, analysis, and interpretation of PRO results. On the basis of the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use E9(R1) addendum, we provide an overview of the estimand framework intended for a multistakeholder audience. We apply the estimand framework to a hypothetical trial for breast cancer, using physical function to develop specific PRO research objectives. This Policy Review is not an endorsement of a specific study design or outcome; rather, it is meant to show the application of principles of the estimand framework to research study design and add to ongoing discussion. Use of the estimand framework to review medical products and label PROs in oncology can improve communication between stakeholders and ultimately provide a clearer interpretation of patient experience in the development of oncological drugs.


Asunto(s)
Protocolos de Ensayos Clínicos como Asunto , Oncología Médica/normas , Medición de Resultados Informados por el Paciente , Antineoplásicos/uso terapéutico , Interpretación Estadística de Datos , Desarrollo de Medicamentos/legislación & jurisprudencia , Desarrollo de Medicamentos/normas , Humanos , Comunicación Interdisciplinaria , Oncología Médica/estadística & datos numéricos , Neoplasias/tratamiento farmacológico , Proyectos de Investigación/normas
12.
Eur Rev Med Pharmacol Sci ; 24(18): 9760-9764, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-33015823

RESUMEN

OBJECTIVE: Patients with cancer are usually immunosuppressive and susceptible to COVID-19 infection. Asymptomatic COVID-19 cases are infective and cannot be identified by symptom-based screening. There is an urgent need to control virus spread by asymptomatic carriers at cancer centres. We aim to describe the characteristics, screening methods, and outcomes of cancer patients with asymptomatic COVID-19 infection and to further explore anti-tumour treatment for this population. PATIENTS AND METHODS: We reviewed patients with cancer who were admitted to Hubei Cancer Hospital in Wuhan from February 1, 2020, to April 4, 2020. We collected demographic data, laboratory findings, treatment information, nucleic acid and serum test results, chest computed tomography (CT) information and survival status of cancer patients diagnosed with asymptomatic COVID-19 infection. RESULTS: A total of 16 cancer patients with asymptomatic COVID-19 infection were confirmed. The most common cancer type was breast cancer. The blood cell counts of most patients were in the normal range. Lymphocytes of 100% of asymptomatic carriers were in the normal range. Thirteen (81.3%) patients were positive for virus-specific IgM antibodies, and three (18.8%) were positive by PCR; only one (6.3%) patient showed novel coronavirus pneumonia features on CT. Three (18.3%) patients died, and the cause of death was considered malignancy caused by delaying anti-tumour treatment. CONCLUSIONS: Our study shows that the lymphocytes of 100% of asymptomatic carriers were in the normal range. This result indicates that the host immunity of asymptomatic carriers is not significantly disrupted by COVID-19. Single PCR detection is not sufficient to screen among asymptomatic individuals, and a combination of PCR tests, serological tests and CT is of great importance. Unless the tumour is life-threatening or rapidly progressing, we advise restarting active anti-tumour therapy after PCR tests become negative.


Asunto(s)
Enfermedades Asintomáticas/epidemiología , Instituciones Oncológicas/estadística & datos numéricos , Infecciones por Coronavirus/diagnóstico , Neumonía Viral/diagnóstico , Anciano , Betacoronavirus , China/epidemiología , Infecciones por Coronavirus/complicaciones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Pandemias , Neumonía Viral/complicaciones , Tasa de Supervivencia
13.
Medicine (Baltimore) ; 99(40): e22544, 2020 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-33019464

RESUMEN

BACKGROUND: Clinical studies have shown that celecoxib can significantly inhibit the development of tumors, and basic experiments and in vitro experiments also provide a certain basis, but it is not clear how celecoxib inhibits tumor development in detail. METHODS: A literature search of all major academic databases was conducted (PubMed, China National Knowledge Internet (CNKI), Wan-fang, China Science and Technology Journal Database (VIP), including the main research on the mechanisms of celecoxib on tumors. RESULTS: Celecoxib can intervene in tumor development and reduce the formation of drug resistance through multiple molecular mechanisms. CONCLUSION: Celecoxib mainly regulates the proliferation, migration, and invasion of tumor cells by inhibiting the cyclooxygenases-2/prostaglandin E2 signal axis and thereby inhibiting the phosphorylation of nuclear factor-κ-gene binding, Akt, signal transducer and activator of transcription and the expression of matrix metalloproteinase 2 and matrix metalloproteinase 9. Meanwhile, it was found that celecoxib could promote the apoptosis of tumor cells by enhancing mitochondrial oxidation, activating mitochondrial apoptosis process, promoting endoplasmic reticulum stress process, and autophagy. Celecoxib can also reduce the occurrence of drug resistance by increasing the sensitivity of cancer cells to chemotherapy drugs.


Asunto(s)
Celecoxib/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Celecoxib/efectos adversos , Celecoxib/uso terapéutico , Proliferación Celular/efectos de los fármacos , Inhibidores de la Ciclooxigenasa 2/efectos adversos , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Dinoprostona/metabolismo , Estrés del Retículo Endoplásmico/efectos de los fármacos , Humanos , Metaloproteinasa 2 de la Matriz/efectos de los fármacos , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/efectos de los fármacos , Metaloproteinasa 9 de la Matriz/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos
14.
Tumour Biol ; 42(10): 1010428320965284, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-33028168

RESUMEN

Glucose, as the main consuming nutrient of the body, faces different destinies in cancer cells. Glycolysis, oxidative phosphorylation, and pentose phosphate pathways produce different glucose-derived metabolites and thus affect cells' bioenergetics differently. Tumor cells' dependency to aerobic glycolysis and other cancer-specific metabolism changes are known as the cancer hallmarks, distinct cancer cells from normal cells. Therefore, these tumor-specific characteristics receive the limelight as targets for cancer therapy. Glutamine, serine, and fatty acid oxidation together with 5-lipoxygenase are main pathways that have attracted lots of attention for cancer therapy. In this review, we not only discuss different tumor metabolism aspects but also discuss the metabolism roles in the promotion of cancer cells at different stages and their difference with normal cells. Besides, we dissect the inhibitors potential in blocking the main metabolic pathways to introduce the effective and non-effective inhibitors in the field.


Asunto(s)
Antineoplásicos/uso terapéutico , Metabolismo Energético/efectos de los fármacos , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Medicina de Precisión , Antineoplásicos/farmacología , Ciclo del Ácido Cítrico/efectos de los fármacos , Metabolismo Energético/efectos de la radiación , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glucosa/metabolismo , Glucólisis/efectos de los fármacos , Humanos , Terapia Molecular Dirigida/métodos , Neoplasias/etiología , Neoplasias/patología , Fosforilación Oxidativa/efectos de los fármacos , Vía de Pentosa Fosfato/efectos de los fármacos , Medicina de Precisión/métodos
15.
Medicine (Baltimore) ; 99(41): e22567, 2020 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-33031304

RESUMEN

BACKGROUND: We put the meta-analysis into practice to reveal the relationship between the incidence risk of immune-related pneumonitis and the use of programmed cell death-1 (PD-1) and ligand 1 (PD-L1) inhibitors related pneumonitis in cancer patients. METHOD: The meta-analysis was put into practice according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Odds ratio (OR) was evaluated by random effect model. RESULTS: After screening and eligibility assessment, 33 clinical trials involving 19,854 patients were selected and used for the final meta-analysis after selection criteria checked. Compared with chemotherapy, the use of PD-1/PD-L1 inhibitors alone increased the incidence risk of all-grade (OR = 4.29, 95% confidence interval: [2.97, 6.19], P < .00001) and grade 3 to 5 immune-related pneumonitis (OR = 3.53, 95% confidence interval: [2.04, 6.11], P < .00001). Similar trend could also be found when PD-1/PD-L1 inhibitors were prescribed alone or in combination with other anti-tumor therapies. CONCLUSION: Whether PD-1/PD-L1 inhibitors were used alone or combined with other antitumor drugs, the incidence risk of immune-related pneumonitis would be increased.


Asunto(s)
Antígeno B7-H1/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Neumonía/inducido químicamente , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Humanos , Neumonía/inmunología
16.
Cancer Sci ; 111(10): 3468-3477, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-33044028

RESUMEN

The effectiveness of current chemotherapies for cancer is gradually progressing; however achieving a complete cure through chemotherapy is still difficult and has been the main goal in treatment of advanced cancer. Drug resistance is an issue in cancer therapy, therefore increasing numbers of investigations into drug resistance have focused on the characteristics of the cancer cells themselves. The interaction between the tumor microenvironment (TME) and cancer cells is also intimately involved in the development of drug resistance. Cancer-associated fibroblasts (CAFs) are a predominant component of the TME and affect tumor progression by secreting soluble factors. This review summarizes the most up-to-date knowledge of CAFs and drug resistance in cancer, with a focus on factors secreted from CAFs including proteins, cytokines, extracellular vesicles, and metabolites. A perspective on the potential role of anti-CAF therapies in overcoming CAF-induced drug resistance is also discussed.


Asunto(s)
Fibroblastos Asociados al Cáncer/metabolismo , Resistencia a Medicamentos , Neoplasias/tratamiento farmacológico , Humanos , Neoplasias/patología , Microambiente Tumoral
17.
Life Sci ; 259: 118395, 2020 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-32905830

RESUMEN

In recent years, natural products have increasingly attracted more attention because of their potential anticancer activity and low intrinsic toxicity. Hispidulin is a natural flavonoid with a wide range of biological activities, including anti-inflammatory, antifungal, antiplatelet, anticonvulsant, anti-osteoporotic, and notably anticancer activities. Numerous in vivo and in vitro studies have shown that hispidulin, as a potential anticancer drug, affects cell proliferation, apoptosis, cell cycle, angiogenesis, and metastasis. Moreover, hispidulin exhibits synergistic anti-tumor effects when combined with some common clinical anticancer drugs (e.g., gemcitabine, 5-fluoroucil, sunitinib, temozolomide, and TRAIL). The combination of hispidulin and chemotherapeutic drugs reduces the efflux of chemotherapeutic drugs, enhances the chemosensitivity of cancer cells, and reverses drug resistance. Herein, we outlined the anticancer effects of hispidulin in various cancers and its intracellular molecular targets and related mechanisms of its anticancer activity. Based on the available literature, it can be established that hispidulin has significant potential to become an important complementary medicine for cancer prevention and treatment. However, more in-depth in vitro and in vivo studies should be conducted to support its translation from bench to bedside.


Asunto(s)
Antineoplásicos/uso terapéutico , Flavonas/uso terapéutico , Flavonoides/uso terapéutico , Neoplasias/tratamiento farmacológico , Animales , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico
19.
Adv Exp Med Biol ; 1274: 203-222, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32894512

RESUMEN

The lipid kinases that generate the lipid signalling phosphoinositides have been established as fundamental signalling enzymes that control numerous aspects of how cells respond to their extracellular environment. In addition, they play critical roles in regulating membrane trafficking and lipid transport within the cell. The class I phosphoinositide kinases which generate the critical lipid signal PIP3 are hyperactivated in numerous human pathologies including cancer, overgrowth syndromes, and primary immunodeficiencies. The type III phosphatidylinositol 4-kinase beta isoform (PI4KB), which are evolutionarily similar to the class I PI3Ks, have been found to be essential host factors mediating the replication of numerous devastating pathogenic viruses. Finally, targeting the parasite variant of PI4KB has been established as one of the most promising strategies for the development of anti-malarial and anti-cryptosporidium strategies. Therefore, the development of targeted isoform selective inhibitors for these enzymes are of paramount importance. The first generation of PI3K inhibitors have recently been clinically approved for a number of different cancers, highlighting their therapeutic value. This review will examine the history of the class I PI3Ks, and the type III PI4Ks, their relevance to human disease, and the structural basis for their regulation and inhibition by potent and selective inhibitors.


Asunto(s)
1-Fosfatidilinositol 4-Quinasa/antagonistas & inhibidores , Enfermedades del Sistema Inmune/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Enfermedades Parasitarias/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Enfermedades de Inmunodeficiencia Primaria/tratamiento farmacológico , Virosis/tratamiento farmacológico , 1-Fosfatidilinositol 4-Quinasa/metabolismo , Animales , Humanos , Enfermedades del Sistema Inmune/enzimología , Neoplasias/enzimología , Enfermedades Parasitarias/enzimología , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Enfermedades de Inmunodeficiencia Primaria/enzimología , Virosis/enzimología
20.
Nat Commun ; 11(1): 4469, 2020 09 08.
Artículo en Inglés | MEDLINE | ID: mdl-32901013

RESUMEN

Dissecting tumor heterogeneity is a key to understanding the complex mechanisms underlying drug resistance in cancers. The rich literature of pioneering studies on tumor heterogeneity analysis spurred a recent community-wide benchmark study that compares diverse modeling algorithms. Here we present FastClone, a top-performing algorithm in accuracy in this benchmark. FastClone improves over existing methods by allowing the deconvolution of subclones that have independent copy number variation events within the same chromosome regions. We characterize the behavior of FastClone in identifying subclones using stage III colon cancer primary tumor samples as well as simulated data. It achieves approximately 100-fold acceleration in computation for both simulated and patient data. The efficacy of FastClone will allow its application to large-scale data and clinical data, and facilitate personalized medicine in cancers.


Asunto(s)
Algoritmos , Variaciones en el Número de Copia de ADN , Neoplasias/genética , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Biología Computacional/métodos , Simulación por Computador , ADN de Neoplasias/genética , Resistencia a Antineoplásicos/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Modelos Genéticos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Filogenia , Medicina de Precisión , Análisis de Secuencia de ADN
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