RESUMEN
Despite the dramatic advances in cancer research over the decades, effective therapeutic strategies are still urgently needed. Increasing evidence indicates that connective tissue growth factor (CTGF), a multifunctional signaling modulator, promotes cancer initiation, progression, and metastasis by regulating cell proliferation, migration, invasion, drug resistance, and epithelial-mesenchymal transition (EMT). CTGF is also involved in the tumor microenvironment in most of the nodes, including angiogenesis, inflammation, and cancer-associated fibroblast (CAF) activation. In this review, we comprehensively discuss the expression of CTGF and its regulation, oncogenic role, clinical relevance, targeting strategies, and therapeutic agents. Herein, we propose that CTGF is a promising cancer therapeutic target that could potentially improve the clinical outcomes of cancer patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Factor de Crecimiento del Tejido Conjuntivo/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Proteínas Oncogénicas/antagonistas & inhibidores , Animales , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Ensayos Clínicos como Asunto , Factor de Crecimiento del Tejido Conjuntivo/genética , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Curcumina/farmacología , Curcumina/uso terapéutico , Progresión de la Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Matriz Extracelular/metabolismo , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Ratones , Neoplasias/genética , Neoplasias/mortalidad , Neoplasias/patología , Proteínas Oncogénicas/genética , Proteínas Oncogénicas/metabolismo , Pronóstico , Transducción de Señal/efectos de los fármacos , Tasa de Supervivencia , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cholangiocarcinoma (CCA) is a malignant tumor that arises from the epithelial cells of the bile duct and is notorious for its poor prognosis. The clinical outcome remains disappointing, and thus more effective therapeutic options are urgently required. Cordycepin, a traditional Chinese medicine, provides multiple pharmacological strategies in antitumors, but its mechanisms have not been fully elucidated. In this study, we reported that cordycepin inhibited the viability and proliferation capacity of CCA cells in a time- and dose-dependent manner determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and colony formation assay. Flow cytometry and Hoechst dye showed that cordycepin induced cancer cell apoptosis via extracellular signal-regulated kinase (ERK) 1/2 deactivation. Moreover, cordycepin significantly reduced the angiogenetic capabilities of CCA in vitro as examined by tube formation assay. We also discovered that cordycepin inhibited DEK expression by using Western blot assay. DEK serves as an oncogenic protein that is overexpressed in various gastrointestinal tumors. DEK silencing inhibited CCA cell viability and angiogenesis but not apoptosis induction determined by Western blot and flow cytometry. Furthermore, cordycepin significantly inhibited tumor growth and angiogenic capacities in a xenograft model by downregulating the expression of DEK, phosphorylated ERK1/2 CD31 and von Willebrand factor (vWF). Taken together, we demonstrated that cordycepin inhibited CCA cell proliferation and angiogenesis with a DEK interaction via downregulation in ERK signaling. These data indicate that cordycepin may serve as a novel agent for CCA clinical treatment and prognosis improvement. SIGNIFICANCE STATEMENT: Cordycepin provides multiple strategies in antitumors, but its mechanisms are not fully elucidated, especially on cholangiocarcinoma (CCA). We reported that cordycepin inhibited the viability of CCA cells, induced apoptosis via extracellular signal-regulated kinase 1/2 deactivation and DEK inhibition, and reduced the angiogenetic capabilities of CCA both in vivo and in vitro.
Asunto(s)
Neoplasias de los Conductos Biliares/tratamiento farmacológico , Colangiocarcinoma/tratamiento farmacológico , Proteínas Cromosómicas no Histona/antagonistas & inhibidores , Desoxiadenosinas/farmacología , Quinasas MAP Reguladas por Señal Extracelular/fisiología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Neovascularización Patológica/prevención & control , Proteínas Oncogénicas/antagonistas & inhibidores , Proteínas de Unión a Poli-ADP-Ribosa/antagonistas & inhibidores , Animales , Neoplasias de los Conductos Biliares/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Colangiocarcinoma/patología , Humanos , Masculino , Ratones , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The NSD family (NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1) are histone lysine methyltransferases (HMTases) essential for chromatin regulation. The NSDs are oncoproteins, drivers of a number of tumors and are considered important drug-targets but the lack of potent and selective inhibitors hampers further therapeutic development and limits exploration of their biology. In particular, MMSET/NSD2 selective inhibition is being pursued for therapeutic interventions against multiple myeloma (MM) cases, especially in multiple myeloma t(4;14)(p16.3;q32) translocation that is associated with a significantly worse prognosis than other MM subgroups. Multiple myeloma is the second most common hematological malignancy, after non-Hodgkin lymphoma and remains an incurable malignancy. Here we report the discovery of LEM-14, an NSD2 specific inhibitor with an in vitro IC50 of 132⯵M and that is inactive against the closely related NSD1 and NSD3. LEM-14-1189, a LEM-14 derivative, differentially inhibits the NSDs with in vitro IC50 of 418⯵M (NSD1), IC50 of 111⯵M (NSD2) and IC50 of 60⯵M (NSD3). We propose LEM-14 and derivative LEM-14-1189 as tools for studying the biology of the NSDs and constitute meaningful steps toward potent NSDs therapeutic inhibitors.
Asunto(s)
Inhibidores Enzimáticos/farmacología , N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , Proteínas Oncogénicas/antagonistas & inhibidores , Proteínas Represoras/antagonistas & inhibidores , Dominio Catalítico , Diseño de Fármacos , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/química , N-Metiltransferasa de Histona-Lisina/química , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Cinética , Modelos Moleculares , Simulación del Acoplamiento Molecular , Estructura Molecular , Conformación Proteica , Proteínas Represoras/química , Proteínas Represoras/genética , Interfaz Usuario-ComputadorRESUMEN
Many human cancer cells contain more than two centrosomes, yet these cancer cells can form pseudo-bipolar spindles through the mechanism, called centrosome clustering, and survive, instead of committing lethal multipolar mitoses. Kinesin-14/HSET, a minus end-directed motor, plays a crucial role in centrosome clustering. Accordingly, HSET is deemed to be a promising chemotherapeutic target to selectively kill cancer cells. Recently, three HSET inhibitors (AZ82, CW069 and SR31527) have been reported, but their specificity and efficacy have not been evaluated rigorously. This downside partly stems from the lack of robust systems for the assessment of these drugs. Yeasts and filamentous fungi provide not only powerful models for basic and applied biology but also versatile tools for drug discovery and evaluation. Here we show that these three inhibitors on their own are cytotoxic to fission yeast, suggesting that they have off-targets in vivo except for kinesin-14. Nonetheless, intriguingly, AZ82 can neutralize otherwise toxic overproduced HSET; this includes a substantial reduction in the percentage of HSET-driven abnormal mitotic cells and partial suppression of its lethality. SR31527 also displays modest neutralizing activity, while we do not detect such activity in CW069. As an experimental proof-of-principle study, we have treated HSET-overproducing fission yeast cells with extracts prepared from various plant species and found activities that rescue HSET-driven lethality in those from Chamaecyparis pisifera and Toxicodendron trichocarpum. This methodology of protein overproduction in fission yeast, therefore, provides a convenient, functional assay system by which to screen for not only selective human kinesin-14 inhibitors but also those against other molecules of interest.
Asunto(s)
Cinesinas/antagonistas & inhibidores , Cinesinas/biosíntesis , Proteínas Oncogénicas/antagonistas & inhibidores , Schizosaccharomyces/genética , Alanina/análogos & derivados , Alanina/farmacología , Evaluación Preclínica de Medicamentos/métodos , Humanos , Cinesinas/genética , Cinesinas/metabolismo , Extractos Vegetales/farmacología , Piridinas/farmacología , Schizosaccharomyces/efectos de los fármacos , Schizosaccharomyces/metabolismo , Proteínas de Schizosaccharomyces pombe/metabolismoRESUMEN
Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that plays a significant role in mitotic progression and cellular responses to DNA damage. While traditionally viewed as a tumor suppressor, inhibition of PP2A has recently come to attention as a novel therapeutic means of driving senescent cancer cells into mitosis and promoting cell death via mitotic catastrophe. These findings have been corroborated in numerous studies utilizing naturally produced compounds that selectively inhibit PP2A. To overcome the known human toxicities associated with these compounds, a water-soluble small molecule inhibitor, LB100, was recently developed to competitively inhibit the PP2A protein. This review summarizes the pre-clinical studies to date that have demonstrated the anti-cancer activity of LB100 via its chemo- and radio-sensitizing properties. These studies demonstrate the tremendous therapeutic potential of LB100 in a variety of cancer types. The results of an ongoing phase 1 trial are eagerly anticipated.
Asunto(s)
Antineoplásicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Inhibidores Enzimáticos/farmacología , Piperazinas/farmacología , Proteína Fosfatasa 2/antagonistas & inhibidores , Fármacos Sensibilizantes a Radiaciones/farmacología , Animales , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Resistencia a Antineoplásicos , Humanos , Mitosis/efectos de los fármacos , Mitosis/genética , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Oncogénicas/antagonistas & inhibidores , Proteínas Oncogénicas/genética , Proteínas Oncogénicas/metabolismo , Proteína Fosfatasa 2/genética , Proteína Fosfatasa 2/metabolismo , Proteína Tumoral Controlada Traslacionalmente 1 , Proteínas Supresoras de Tumor/antagonistas & inhibidores , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
BACKGROUND: Once a promising drug target is identified, the steps to actually discover and optimize a drug are diverse and challenging. OBJECTIVE: The goal of this study was to provide a road map to navigate drug discovery. METHODS: Review general steps for drug discovery and provide illustrating references. RESULTS: A number of approaches are available to enhance and accelerate target identification and validation. Consideration of a variety of potential mechanisms of action of potential drugs can guide discovery efforts. The hit to lead stage may involve techniques such as high-throughput screening, fragment-based screening, and structure-based design, with informatics playing an ever-increasing role. Biologically relevant screening models are discussed, including cell lines, 3-dimensional culture, and in vivo screening. The process of enabling human studies for an investigational drug is also discussed. CONCLUSIONS: Drug discovery is a complex process that has significantly evolved in recent years.
Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Drogas en Investigación/farmacología , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica , Línea Celular Tumoral , Biología Computacional , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Drogas en Investigación/uso terapéutico , Ensayos Analíticos de Alto Rendimiento , Humanos , Simulación del Acoplamiento Molecular , Neoplasias/genética , Proteínas Oncogénicas/antagonistas & inhibidores , Proteínas Oncogénicas/genética , Proteínas Oncogénicas/metabolismo , Reproducibilidad de los Resultados , Estados Unidos , United States Food and Drug AdministrationRESUMEN
The aberrant hedgehog (Hh)/GLI signaling pathway causes the formation and progression of a variety of tumors. By screening tropical plant extracts by using our screening system, Zizyphus cambodiana was found to include Hh/GLI signaling inhibitors. Bioassay-guided fractionation of this plant extract led to the isolation of three active pentacyclic triterpenes, colubrinic acid (1), betulinic acid (2) and alphitolic acid (3), as potent inhibitors. The inhibition of GLI-related protein expression with 1 or 2 was observed in HaCaT cells with exogenous GLI1, or human pancreatic cancer cells (PANC1), which express Hh/GLI components aberrantly. The expressions of GLI-related proteins PTCH and BCL2 were clearly inhibited by 1 or 2. We also examined the cytotoxicity of these active compounds against PANC1, human prostate cancer cells (DU145) and mouse embryo fibroblast cells (C3H10T1/2). The cytotoxicity against cancer cells (PANC1 and DU145) by 1 or 2 would be caused by inhibition of the expression of the anti-apoptosis protein BCL2. These pentacyclic triterpene inhibitors showed an important relationship between Hh/GLI signaling inhibition, the decrease of BCL2, and cytotoxicity against cancer cells.
Asunto(s)
Proteínas Oncogénicas/antagonistas & inhibidores , Extractos Vegetales/farmacología , Receptores de Superficie Celular/antagonistas & inhibidores , Transactivadores/antagonistas & inhibidores , Transcripción Genética/efectos de los fármacos , Ziziphus/química , Animales , Western Blotting , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Fibroblastos/efectos de los fármacos , Humanos , Masculino , Maitansina/análogos & derivados , Maitansina/química , Maitansina/farmacología , Ratones , Proteínas Oncogénicas/genética , Proteínas Oncogénicas/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Receptores Patched , Receptor Patched-1 , Triterpenos Pentacíclicos , Fenoles/química , Fenoles/farmacología , Alcohol Feniletílico/análogos & derivados , Alcohol Feniletílico/química , Alcohol Feniletílico/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transactivadores/genética , Transactivadores/metabolismo , Triterpenos/química , Triterpenos/farmacología , Proteína con Dedos de Zinc GLI1 , Dedos de Zinc , Ácido BetulínicoRESUMEN
The aberrant hedgehog (Hh)/GLI signaling pathway causes the formation and progression of a variety of tumors. To search for Hh/GLI inhibitors, we screened for naturally occurring inhibitors of the transcriptional activator GLI1 by using a cell-based assay. We identified zerumbone (1), zerumbone epoxide (2), staurosporinone (9), 6-hydroxystaurosporinone (10), arcyriaflavin C (11) and 5,6-dihydroxyarcyriaflavin A (12) as inhibitors of GLI-mediated transcription. In addition, we isolated physalins F (17) and B (18) from Physalis minima, which are also potent inhibitors. These compounds also inhibited GLI2-mediated transactivation. Semiquantitative RT-PCR and Western blotting analysis further revealed that 1, 9, 17, and 18 decreased Hh-related component expressions. We also show that inhibitors of GLI-mediated transactivation reduce the level of the antiapoptosis Bcl2 expression. Finally, these identified compounds were cytotoxic to PANC1 pancreatic cancer cells, which express Hh/GLI components. These results strongly suggest that the cytotoxicity of the compounds to PANC1 cells correlates with their inhibition of GLI-mediated transcription.
Asunto(s)
Productos Biológicos/química , Productos Biológicos/farmacología , Proteínas Hedgehog/antagonistas & inhibidores , Proteínas Oncogénicas/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Transactivadores/antagonistas & inhibidores , Transcripción Genética/efectos de los fármacos , Animales , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteínas Hedgehog/metabolismo , Humanos , Concentración 50 Inhibidora , Proteínas Oncogénicas/metabolismo , Extractos Vegetales/química , Extractos Vegetales/farmacología , Transducción de Señal/efectos de los fármacos , Transactivadores/metabolismo , Activación Transcripcional/efectos de los fármacos , Proteína con Dedos de Zinc GLI1RESUMEN
Given the poor results with currently available therapies, it is imperative that new treatments be developed for patients with advanced prostate cancer. The next generation of therapies will include many novel biologic agents targeted at molecular defects in the cancer cell. Investigating the efficacy and safety of these compounds and evaluating their utility in combination with traditional therapies such as chemotherapy or radiotherapy are major goals of prostate cancer clinical research for the next decade.