RESUMEN
Pancreatic cancer is a fatal illness caused by mutations in multiple genes. Pancreatic cancer damages the organ that helps in digestion, resulting in symptoms including fatigue, bloating, and nausea. The use of medicinal plants has been crucial in the treatment of numerous disorders. The medicinal plant Calliandra Harrisi has been widely exploited for its possibilities in biology and medicine. The current study aimed to assess the biopotential of biologically active substances against pancreatic cancer. The GC-MS data of these phytochemicals from Calliandra Harrisi were further subjected to computational approaches with pancreatic cancer genes to evaluate their potential as therapeutic candidates. Molecular docking analysis revealed that N-[Carboxymethyl] maleamic acid is the leading molecule responsible for protein denaturation inhibition, having the highest binding affinity of 6.8â¯kJ/mol among all other compounds with KRAS inflammatory proteins. Furthermore, ADMET analysis and Lipinski's rule validation were also performed revealing its higher absorption in the gastrointestinal tract. The results of the hepatotoxicity test demonstrated that phytochemicals are non-toxic, safe to use, and do not cause necrosis, fibrosis, or vacuolar degeneration even at excessive levels. Calliandra Harrisi has phytoconstituents that have a variety of pharmacological uses in consideration.
Asunto(s)
Diseño de Fármacos , Cromatografía de Gases y Espectrometría de Masas , Simulación del Acoplamiento Molecular , Neoplasias Pancreáticas , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Humanos , Medicina de Precisión/métodos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Plantas Medicinales/química , Plantas Medicinales/genética , Simulación por Computador , Fitoquímicos/química , Fitoquímicos/farmacologíaRESUMEN
Ageing is one of the major risk factors of human diseases, including cancer, diabetes, and cardiovascular disease. Mulberry exhibits a wide range of functions, such as anti-oxidant, anti-inflammation, and anti-diabetes. In this study, we investigated the role of mulberry polyphenol extract (MPE) in K-Ras-induced senescence of smooth muscle cells. Forced expression of K-Ras enhanced senescence of smooth muscle A7r5 cells as shown by the elevation of ß-galactosidase activity. Treatment with MPE significantly repressed the Ras, phosphorylated ERK, and ß-galactosidase level. MPE triggered the association of cyclins with their corresponding cyclin-dependent protein kinases and hyperphosphorylated retinoblastoma (RB). MPE also down-regulated the levels of K-Ras-induced CDK inhibitors. MPE enhanced the phosphorylated AMP-dependent protein kinase (AMPK) and inducible nitric oxide synthase (iNOS) level in the presence of K-Ras. Pretreatment with either L-NAME or AMPK inhibitor reversed the effects of MPE. In addition, L-NAME and AMPK inhibitor repressed the MPE-induced total and phosphorylated 3-hydroxy-3-methylglutaryl coenzyme A (HMG-Co A) level. MPE repressed K-Ras-induced G0/G1 arrest, whereas L-NAME and AMPK inhibitor blocked the effects of MPE. Our results indicated that MPE recovered the K-Ras-induced senescence of vascular smooth muscle cells through iNOS and AMPK-dependent pathway. Our findings suggested that MPE may prevent ageing-induced atherosclerosis.
Asunto(s)
Senescencia Celular/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Morus/química , Músculo Liso Vascular/citología , Miocitos del Músculo Liso/efectos de los fármacos , Extractos Vegetales/farmacología , Polifenoles/farmacología , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Acilcoenzima A/metabolismo , Células Cultivadas , Expresión Génica , Humanos , Miocitos del Músculo Liso/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Fosforilación , Proteolisis , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , beta-Galactosidasa/metabolismoRESUMEN
Sotorasib is a first-in-class KRASG12C covalent inhibitor in clinical development for the treatment of tumors with the KRAS p.G12C mutation. A comprehensive nonclinical safety assessment package, including secondary/safety pharmacology and toxicology studies, was conducted to support the marketing application for sotorasib. Sotorasib was negative in a battery of genotoxicity assays and negative in an in vitro phototoxicity assay. Based on in vitro assays, sotorasib had no off-target effects against various receptors, enzymes (including numerous kinases), ion channels, or transporters. Consistent with the tumor-specific target distribution (ie, KRASG12C), there were no primary pharmacology-related on-target effects identified. The kidney was identified as a target organ in the rat but not the dog. Renal toxicity in the rat was characterized by tubular degeneration and necrosis restricted to a specific region suggesting that the toxicity was attributed to the local formation of a putative toxic reactive metabolite. In the 3-month dog study, adaptive changes of hepatocellular hypertrophy due to drug metabolizing enzyme induction were observed in the liver that was associated with secondary effects in the pituitary and thyroid gland. Sotorasib was not teratogenic and had no direct effect on embryo-fetal development in the rat or rabbit. Human, dog, and rat circulating metabolites, M24, M10, and M18, raised no clinically relevant safety concerns based on the general toxicology studies, primary/secondary pharmacology screening, an in vitro human ether-à-go-go-related gene assay, or mutagenicity assessment. Overall, the results of the nonclinical safety program support a high benefit/risk ratio of sotorasib for the treatment of patients with KRAS p.G12C-mutated tumors.
Asunto(s)
Antineoplásicos/toxicidad , Piperazinas/toxicidad , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Piridinas/toxicidad , Pirimidinas/toxicidad , Animales , Antineoplásicos/farmacología , Evaluación Preclínica de Medicamentos , Humanos , Mutación , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Piperazinas/farmacología , Piridinas/farmacología , Pirimidinas/farmacologíaRESUMEN
RAS, TP53 (p53) and MYC are among the most frequently altered driver genes in cancer. Thus, RAS is the most frequently mutated oncogene, MYC the most frequently amplified gene and TP53 the most frequently mutated tumor suppressor gene and overall the most frequently mutated gene in cancer. Theoretically, therefore, these genes are highly attractive targets for cancer treatment. However, as the protein products of each of these genes lack an accessible hydrophobic pocket into which low molecular weight compounds might bind with high affinity, they have proved difficult to target and have traditionally been referred to as "undruggable." Despite this branding, several low molecular weight compounds targeting each of these proteins have recently been reported to have anticancer activity in preclinical models. Indeed, several drugs inhibiting mutant KRAS, MYC overexpression or reactivating mutant p53 have undergone or are currently undergoing clinical trials. For targeting mutant KRAS and reactivating mutant p53, trials have progressed to a Phase III stage, that is, the mutant-p53 reactivating drug, APR-246 is currently being investigated in patients with myelodysplastic syndrome (MDS) and the RAS inhibitor, rigosertib is also undergoing evaluation in patients with MDS. Although there appears to be no directly acting MYC inhibitor currently being tested in a clinical trial, an anti-MYC compound, known as OmoMYC has been extensively validated in multiple preclinical models and is being developed for clinical evaluation. Based on current evidence, the traditional perception of RAS, p53 and MYC as being "undruggable" would appear to be coming to an end.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-myc/antagonistas & inhibidores , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/agonistas , Animales , Antineoplásicos/uso terapéutico , Sitios de Unión , Carcinogénesis/efectos de los fármacos , Carcinogénesis/genética , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ratones , Mutación , Neoplasias/genética , Proteínas Proto-Oncogénicas c-myc/química , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas p21(ras)/química , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteína p53 Supresora de Tumor/química , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Drugs that target KRAS 12C covalently, AMG 510 and MRTX849, are now in the clinic. Recent papers describe development of these compounds, their selectivity and properties, early clinical data, and potential combination therapies. These papers herald a new era in Ras research, with improved drugs and strategies certain to follow.
Asunto(s)
Antineoplásicos/farmacología , Genes ras , Piperazinas/farmacología , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Piridinas/farmacología , Pirimidinas/farmacología , Animales , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Mutación , Neoplasias/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Investigación Biomédica Traslacional , Resultado del TratamientoRESUMEN
Pancreatic cancer is a highly malignant tumor with a 5-year survival rate of less than 6%, and incidence increasing year by year globally. Pancreatic cancer has a poor prognosis and a high recurrence rate, almost the same as the death rate. However, the available effective prevention and treatment measures for pancreatic cancer are still limited. The genome variation is one of the main reasons for the development of pancreatic cancer. In recent years, with the development of gene sequencing technology, in-depth research on pancreatic cancer gene mutation presents that a growing number of genetic mutations are confirmed to be in a close relationship with invasion and metastasis of pancreatic cancer. Among them, KRAS mutation is a special one. Therefore, it is particularly important to understand the mechanism of the KRAS mutation in the occurrence and development of pancreatic cancer, and to explore the method of its transformation into clinical tumor molecular targeted treatment sites, to further improve the therapeutic effect on pancreatic cancer. Therefore, to better design chemical drugs, this review based on the biological functions of KRAS, summarized the types of KRAS mutations and their relationship with pancreatic cancer and included the downstream signaling pathway Raf-MEK-ERK, PI3K-AKT, RalGDS-Ral of KRAS and the current medicinal treatment methods for KRAS mutations. Moreover, drug screening and clinical treatment for KRAS mutated cell and animal models of pancreatic cancer are also reviewed along with the prospect of targeted medicinal chemistry therapy for precision treatment of pancreatic cancer in the future.
Asunto(s)
Antineoplásicos/uso terapéutico , Mutación , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Antineoplásicos/farmacología , Evaluación Preclínica de Medicamentos , Humanos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidoresRESUMEN
The aim of this study was to investigate the ameliorative effects of selenium-enriched yeast (Se-yeast) on the inflammatory damage induced by lead (Pb) in chicken skeletal muscles. A total of 108 1-day-old broiler chickens were randomly allocated into four groups (n = 27/group): the control group (C group), the Se-yeast-supplemented group (Se group), the lead-treated group (Pb group), and finally the Se- and Pb-combined group (Pb/Se group). The C group was fed with a basic diet comprising 0.049 mg/kg Se and 0.1 mg/kg Pb while the Se group was fed a Se-yeast diet containing 0.30 mg/kg Se and 0.1 mg/kg Pb. Similarly, the Pb group was fed a Pb acetate diet containing 0.049 mg/kg Se and 350 mg/kg Pb while the Pb/Se group was fed with a Se-yeast diet containing 0.30 mg/kg Se and 350 mg/kg Pb. On days 7, 21, and 35 after commencing the experiment, nine chicks belonging to each group were euthanized and the samples were analyzed by employing the techniques of inductively coupled plasma mass spectrometry and real-time quantitative PCR, along with Western blotting. The results indicated that excess Pb increased the nitric oxide concentration, enhanced the activity of inducible nitric oxide synthase (iNOS), and the mRNA levels of interleukin 1ß (IL-1ß), interleukin 4 (IL-4), interleukin 10 (IL-10), and interferon gamma (IFN-γ) in a time-dependent manner. Further, it was found that Se reduced damage caused by Pb by decreasing the expression of inflammatory factors in chicken skeletal muscles. Taken together, the results from this study provide the theoretical basis for an alleviate effect of Se on Pb-induced inflammatory damage in chicken skeletal muscles, mediated by inhibiting the Ras/extracellular signal-regulated kinase (ERK) pathway and the inflammatory factors.
Asunto(s)
Citocinas/antagonistas & inhibidores , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Selenio/farmacología , Levadura Seca/metabolismo , Animales , Pollos , Citocinas/metabolismo , Suplementos Dietéticos , Plomo/sangre , Plomo/toxicidad , Músculo Esquelético/metabolismo , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Selenio/administración & dosificación , Selenio/sangre , Levadura Seca/administración & dosificaciónRESUMEN
Protein catalyzed capture agents (PCCs) are synthetic antibody surrogates that can target a wide variety of biologically relevant proteins. As a step toward developing a high-throughput PCC pipeline, we report on the preparation of a barcoded rapid assay platform for the analysis of hits from PCC library screens. The platform is constructed by first surface patterning a micrometer scale barcode composed of orthogonal ssDNA strands onto a glass slide. The slide is then partitioned into microwells, each of which contains multiple copies of the full barcode. Biotinylated candidate PCCs from a click screen are assembled onto the barcode stripes using a complementary ssDNA-encoded cysteine-modified streptavidin library. This platform was employed to evaluate candidate PCC ligands identified from an epitope targeted in situ click screen against the two conserved allosteric switch regions of the Kirsten rat sarcoma (KRas) protein. A single microchip was utilized for the simultaneous evaluation of 15 PCC candidate fractions under more than a dozen different assay conditions. The platform also permitted more than a 10-fold savings in time and a more than 100-fold reduction in biological and chemical reagents relative to traditional multiwell plate assays. The best ligand was shown to exhibit an in vitro inhibition constant (IC50) of â¼24 µM.
Asunto(s)
Regulación Alostérica/efectos de los fármacos , ADN de Cadena Simple/química , Inhibidores Enzimáticos/farmacología , Análisis por Micromatrices/métodos , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Sitio Alostérico/efectos de los fármacos , Biotinilación , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/química , Humanos , Proteínas Proto-Oncogénicas p21(ras)/química , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Estreptavidina/químicaRESUMEN
Since the successful exfoliation of graphene from graphite in 2004, graphene and graphene oxide (GO) have been considered the most promising two-dimensional (2D) nanomaterials with distinguished physical and chemical characteristics and have attracted great attention in many different fields. Graphene oxide is well-known for its distinct physiochemical properties and shows only minimal cytotoxicity compared to carbon nanotubes. Until now, only limited efforts have been invested in utilizing GO for gene therapy in pancreatic cancer treatments. In this study, we utilized multi-functionalized monolayer GO as a gene delivery system to efficiently co-deliver HDAC1 and K-Ras siRNAs (small interfering RNAs targeting the HDAC1 gene and the G12C mutant K-Ras gene, respectively) to specifically target pancreatic cancer cells MIA PaCa-2. The systematic mechanistic elucidation of the dual gene silencing effects indicated the inactivation of both the HDAC1 and the K-Ras gene, thereby causing apoptosis, proliferation inhibition and cell cycle arrest in treated MIA PaCa-2 cells. The synergistic combination of gene silencing and NIR light thermotherapy showed significant anticancer efficacy, inhibiting in vivo tumor volume growth by >80%. Furthermore, GO can be metabolized in the mouse model within a reasonable period of time without obvious side effects. Based on preliminary in vivo application, this study for the first time indicates the promising potential of functionalized GO as a vehicle for gene therapy delivery with low toxicity for the treatment of pancreatic adenocarcinoma.
Asunto(s)
Productos Biológicos/administración & dosificación , Portadores de Fármacos/administración & dosificación , Grafito/administración & dosificación , Nanoestructuras/administración & dosificación , Óxidos/administración & dosificación , Neoplasias Pancreáticas/terapia , ARN Interferente Pequeño/administración & dosificación , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Modelos Animales de Enfermedad , Células Epiteliales/efectos de los fármacos , Células Epiteliales/fisiología , Células Epiteliales/efectos de la radiación , Terapia Genética/métodos , Histona Desacetilasa 1/antagonistas & inhibidores , Hipertermia Inducida/métodos , Rayos Infrarrojos , Ratones , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidoresRESUMEN
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive tumors with low survival rates and the leading cause of death in neurofibromatosis type 1 (NF1) patients under 40 years old. Surgical resection is the standard of care for MPNSTs, but is often incomplete and can generate loss of function, necessitating the development of novel treatment methods for this patient population. Here, we describe a novel combination therapy comprising MEK inhibition and nanoparticle-based photothermal therapy (PTT) for MPNSTs. MEK inhibitors block activity driven by Ras, an oncogene constitutively activated in NF1-associated MPNSTs, while PTT serves as a minimally invasive method to ablate cancer cells. Our rationale for combining these seemingly disparate techniques for MPNSTs is based on several reports demonstrating the efficacy of systemic chemotherapy with local PTT. We combine the MEK inhibitor, PD-0325901 (PD901), with Prussian blue nanoparticles (PBNPs) as PTT agents, to block MEK activity and simultaneously ablate MPNSTs. Our data demonstrate the synergistic effect of combining PD901 with PBNP-based PTT, which converge through the Ras pathway to generate apoptosis, necrosis, and decreased proliferation, thereby mitigating tumor growth and increasing survival of MPNST-bearing animals. Our results suggest the potential of this novel local-systemic combination "nanochemotherapy" for treating patients with MPNSTs.
Asunto(s)
Benzamidas/uso terapéutico , Difenilamina/análogos & derivados , Hipertermia Inducida/métodos , Rayos Infrarrojos/uso terapéutico , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Nanopartículas/uso terapéutico , Neurilemoma/terapia , Neurofibromatosis 1 , Inhibidores de Proteínas Quinasas/uso terapéutico , Animales , Benzamidas/farmacología , Línea Celular Tumoral , Difenilamina/farmacología , Difenilamina/uso terapéutico , Modelos Animales de Enfermedad , Ensayos de Selección de Medicamentos Antitumorales , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Ferrocianuros , Terapia por Láser/métodos , Ratones , Nanopartículas/efectos de la radiación , Proteínas de Neoplasias/antagonistas & inhibidores , Neurilemoma/tratamiento farmacológico , Neurilemoma/genética , Neurofibromatosis 1/genética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Resonancia por Plasmón de SuperficieRESUMEN
Lung cancer is the leading cause of cancer-related deaths worldwide, and even today, the 5-year survival rate is still below 15%. Lung adenocarcinoma is the most frequent subtype, and approximately 25% of the cases harbor activating mutations in the KRAS gene. To date, there is no effective treatment for patients carrying KRAS mutations due, at least in part, to the challenge posed by direct targeting of the KRAS oncoprotein. During the last decade, scientists have developed genetically engineered mouse models that faithfully recapitulate the natural history of the human tumors. These models have been used as a preclinical platform to validate a number of relevant downstream effectors of KRAS signaling. Targets displaying synthetic lethality with the KRAS oncoprotein have also been validated in these models. Here, we review these studies and discuss their potential value in the clinical setting. We also provide an outlook as of how to improve the significance of target validation studies in preclinical platforms.
Asunto(s)
Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Adenocarcinoma del Pulmón , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Ciclo Celular/efectos de los fármacos , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Resistencia a Antineoplásicos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Sistema de Señalización de MAP Quinasas , Ratones , Terapia Molecular Dirigida , Mutación , Metástasis de la Neoplasia , Oncogenes , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacosRESUMEN
Colorectal cancer (CRC) is a global health problem with profound mortality and morbidity effects particularly in the advanced/metastatic setting. Because of the recent understanding of the biology of this disease, many candidate targets have come into light for therapeutic evaluation. The current review is about evaluating the preclinical and clinical aspects of BRAF as a therapeutic target in this disease. The available clinical results suggest that while the use of unselective RAF inhibitors (e.g., sorafenib) has been ineffective in the management of advanced CRC patients with KRAS mutation, combination of selective BRAF inhibitors plus EGFR inhibitors may represent a good therapeutic strategy in BRAF-mutant CRC.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Receptores ErbB/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Resistencia a Antineoplásicos , Receptores ErbB/antagonistas & inhibidores , Humanos , Terapia Molecular Dirigida , Mutación , Estadificación de Neoplasias , Niacinamida/análogos & derivados , Niacinamida/uso terapéutico , Compuestos de Fenilurea/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , SorafenibRESUMEN
Despite extensive efforts to target mutated RAS proteins, anticancer agents capable of selectively killing tumour cells harbouring KRAS mutations have remained unavailable. Here we demonstrate the direct targeting of KRAS mutant DNA using a synthetic alkylating agent (pyrrole-imidazole polyamide indole-seco-CBI conjugate; KR12) that selectively recognizes oncogenic codon 12 KRAS mutations. KR12 alkylates adenine N3 at the target sequence, causing strand cleavage and growth suppression in human colon cancer cells with G12D or G12V mutations, thus inducing senescence and apoptosis. In xenograft models, KR12 infusions induce significant tumour growth suppression, with low host toxicity in KRAS-mutated but not wild-type tumours. This newly developed approach may be applicable to the targeting of other mutant driver oncogenes in human tumours.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Imidazoles/síntesis química , Imidazoles/uso terapéutico , Neoplasias Experimentales/tratamiento farmacológico , Nylons/síntesis química , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Células CACO-2 , Senescencia Celular/efectos de los fármacos , Daño del ADN , Evaluación Preclínica de Medicamentos , Femenino , Células HT29 , Humanos , Imidazoles/farmacología , Ratones Desnudos , Mutación , Nylons/farmacología , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
INTRODUCTION: Sorafenib monotherapy has shown benefits in phase II trials as third-/fourth-line treatment in patients with non-small-cell lung cancer (NSCLC). METHODS: The phase III, multinational, double-blind, placebo-controlled Monotherapy admInistration of Sorafenib in patientS wIth nOn-small-cell luNg cancer (MISSION) trial randomized patients with advanced relapsed/refractory NSCLC, following two or three prior treatment regimens, to sorafenib 400 mg twice a day (n = 350) or matching placebo (n = 353) plus best supportive care. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS) and time to progression. Epidermal growth factor receptor and KRAS mutation status was analyzed in archival tumor and/or circulating tumor DNA from blood samples obtained during screening. RESULTS: Median OS was similar in the sorafenib and placebo groups (8.2 versus 8.3 mo; hazard ratio [HR], 0.99; 95% confidence interval [CI], 0.84-1.17; p = 0.47). Median PFS (2.8 versus 1.4 mo; HR, 0.61; 95% CI, 0.51-0.72; p < 0.0001), and time to progression (2.9 versus 1.4 mo; HR, 0.54; 95% CI, 0.45-0.65; p < 0.0001) were significantly greater with sorafenib than with placebo. Among the 89 patients with epidermal growth factor receptor mutations, OS (13.9 versus 6.5 mo; HR, 0.48; 95% CI, 0.30-0.76; p = 0.002) and PFS (2.7 versus 1.4 mo; HR, 0.27; 95% CI, 0.16-0.46; p < 0.001) were significantly higher with sorafenib than placebo. PFS was significantly longer with sorafenib than placebo in patients with either wild-type or mutated KRAS, but OS was similar. Common drug-related adverse events were rash/desquamation, diarrhea, and fatigue, consistent with the safety profile of sorafenib. CONCLUSIONS: Third-/fourth-line sorafenib therapy did not significantly increase OS in patients with relapsed/refractory NSCLC, despite significantly increasing PFS.
Asunto(s)
Antineoplásicos/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Método Doble Ciego , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Femenino , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Mutación , Niacinamida/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Proteínas Proto-Oncogénicas p21(ras)/genética , Sorafenib , Resultado del TratamientoRESUMEN
Aberrant signaling by oncogenic mutant rat sarcoma (Ras) proteins occurs in â¼15% of all human tumors, yet direct inhibition of Ras by small molecules has remained elusive. Recently, several small-molecule ligands have been discovered that directly bind Ras and inhibit its function by interfering with exchange factor binding. However, it is unclear whether, or how, these ligands could lead to drugs that act against constitutively active oncogenic mutant Ras. Using a dynamics-based pocket identification scheme, ensemble docking, and innovative cell-based assays, here we show that andrographolide (AGP)--a bicyclic diterpenoid lactone isolated from Andrographis paniculata--and its benzylidene derivatives bind to transient pockets on Kirsten-Ras (K-Ras) and inhibit GDP-GTP exchange. As expected for inhibitors of exchange factor binding, AGP derivatives reduced GTP loading of wild-type K-Ras in response to acute EGF stimulation with a concomitant reduction in MAPK activation. Remarkably, however, prolonged treatment with AGP derivatives also reduced GTP loading of, and signal transmission by, oncogenic mutant K-RasG12V. In sum, the combined analysis of our computational and cell biology results show that AGP derivatives directly bind Ras, block GDP-GTP exchange, and inhibit both wild-type and oncogenic K-Ras signaling. Importantly, our findings not only show that nucleotide exchange factors are required for oncogenic Ras signaling but also demonstrate that inhibiting nucleotide exchange is a valid approach to abrogating the function of oncogenic mutant Ras.
Asunto(s)
Andrographis/química , Diterpenos/farmacología , Neoplasias/tratamiento farmacológico , Preparaciones de Plantas/farmacología , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Sitios de Unión/efectos de los fármacos , Simulación por Computador , Diterpenos/química , Guanosina Trifosfato/metabolismo , Modelos Químicos , Neoplasias/metabolismo , Preparaciones de Plantas/química , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas p21(ras)/química , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Ratas , Factores de Intercambio de Guanina Nucleótido ras/metabolismoRESUMEN
OBJECTIVE: Preliminary studies have demonstrated that the Ras family and related guanosine triphosphate-dependent proteins are overactivated in malignant gliomas and that inhibition of the activation of such proteins, by blockade of their post-translational processing, reduces tumor cell growth in vitro. The current study evaluates the utility of this therapeutic strategy in vivo, using preclinical glioma model systems. METHODS: We examined the efficacy against U-87 human malignant glioma cells, in both subcutaneous and intracranial nude mouse models, of selective peptidomimetic inhibitors of farnesyltransferase (FTI-276) and geranylgeranyltransferase (GGTI-297), which are involved in critical steps in the post-translational processing of Ras and related guanosine triphosphate-dependent proteins. For the subcutaneous model, 2 x 10(5) U-87 cells were implanted; after measurable tumors were detected on Day 7, animals were treated with either FTI-276, GGTI-297, or vehicle, administered by continuous infusion for 7 days. Differences in tumor volumes among the treatment groups were examined for significance using a Student's t test. For the intracranial model, 2 x 10(5) U-87 cells were implanted in the right frontal lobe and treatment was initiated on Day 7. In initial studies, animals received a 7-day course of either FTI-276, GGTI-297, or vehicle. In subsequent studies, a 28-day treatment period was used. Comparisons of survival times among treatment groups were performed using a rank-sum test. RESULTS: Although the two agents exhibited comparable antiproliferative activities in previous in vitro studies, an obvious difference in efficacy was apparent in this study. Whereas the geranylgeranyltransferase inhibitor failed to improve survival rates, compared with those observed for control animals, in either the subcutaneous or intracranial model, the farnesyltransferase inhibitor produced objective regression of tumor growth in the subcutaneous model and significant prolongation of survival times in the intracranial model, without apparent toxicity. In the subcutaneous model, tumor volumes for the control, GGTI-297-treated, and FTI-276-treated animals on Day 28 after implantation were 621+/-420, 107+/-104, and 18.5+/-12.7 mm3, respectively (P < 0.05). In the 7-day-treated intracranial model, survival times for the control, GGTI-297-treated, and FTI-276-treated groups were 27.7+/-2.9, 29.8+/-2.1, and 43.6+/-2.7 days, respectively (P < 0.001). In the 28-day-treated intracranial model, survival times for the control, GGTI-297-treated, and FTI-276-treated groups were 29.2+/-3.7, 28.3+/-3.9, and 58.7+/-6.2 days, respectively, with five of six animals in the latter group surviving more than 55 days after tumor implantation (P < 0.001). CONCLUSION: These studies demonstrate that farnesyltransferase inhibition is effective in diminishing the growth of human glioma cells in vivo. Evaluation of this treatment approach in clinical trials is warranted.