RESUMEN
Osteoarthritis (OA) is a highly prevalent chronic joint disease that involves extracellular matrix (ECM) degradation and articular cartilage inflammation. Polydatin (PD) can alleviate inflammatory reactions in numerous diseases. The present study aimed to investigate the chondroprotective and anti-inflammatory effects of PD on interleukin (IL)- 1ß-treated chondrocytes in vitro and anterior cruciate ligament transection-induced rat OA models in vivo. Primary chondrocytes were isolated from SD rats and cultured. Only second-passage cells were used for subsequent experiments. Counting kit-8, quantitative real-time polymerase chain reaction, western blotting, enzyme-linked immunosorbent assay, and immunofluorescence were used to detect relevant indices. Rat OA models were established to obtain in vivo data. PD treatment decreased the production of nitric oxide (NO), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and IL-6 during IL-1ß-stimulated chondrocyte inflammation. Moreover, PD upregulated aggrecan and collagen II expression, whereas downregulated a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) and matrix metalloproteinase-13 (MMP-13) expression on IL-1ß-mediated chondrocytes. Additionally, PD reduced IL-1ß-stimulated NF-κB and Wnt/ß-catenin activation and nuclear translocation. The results of histological analysis and scoring revealed that OA in the rat models was effectively ameliorated by the intra-articular injection of PD. PD suppressed IL-1ß-stimulated iNOS, COX-2, NO, and PGE2 production, TNF-α, IL-6, collagen X, MMP-13, and ADAMTS-5 expression, collagen II and aggrecan degeneration by inhibiting NF-κB and Wnt/ß-catenin signaling in vitro. PD also mitigated OA progression in the rat models, thereby providing reliable data that PD could serve as a promising candidate for OA therapy.
Asunto(s)
Cartílago Articular , Condrocitos , Agrecanos , Animales , Antiinflamatorios/farmacología , Cartílago Articular/metabolismo , Células Cultivadas , Ciclooxigenasa 2 , Dinoprostona/metabolismo , Dinoprostona/farmacología , Dinoprostona/uso terapéutico , Desintegrinas/metabolismo , Desintegrinas/farmacología , Desintegrinas/uso terapéutico , Glucósidos , Inflamación/metabolismo , Interleucina-6/farmacología , Metaloproteinasa 13 de la Matriz/metabolismo , Metaloproteinasa 13 de la Matriz/farmacología , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ratas , Ratas Sprague-Dawley , Estilbenos , Trombospondinas/metabolismo , Trombospondinas/farmacología , Trombospondinas/uso terapéutico , Factor de Necrosis Tumoral alfa/metabolismo , Vía de Señalización Wnt , beta Catenina/metabolismoRESUMEN
BACKGROUND/OBJECTIVES: A disintegrin and metalloproteinase domain-containing protein 12 (ADAM12) has been reported to influence tumor progression and chemosensitivity in human cancers. We assessed the prognostic impact of ADAM12 and its predictive value for neoadjuvant chemotherapy (NAC) in patients with pancreatic ductal adenocarcinoma (PDAC) treated with surgical resection. METHODS: ADAM12 expression was immunohistochemically examined in 428 patients with PDAC who underwent surgical resection. The association of ADAM12 expression with clinicopathological factors and survival was also analyzed. RESULTS: Patients with high ADAM12 expression exhibited significantly shorter median disease-free survival (DFS) (high ADAM12: 17.8 vs. low ADAM12: 37.9 months; P < 0.001) and overall survival (OS) (high ADAM12: 33.1 vs. low ADAM12: 65.0 months; P < 0.001). A multivariate analysis revealed that high ADAM12 expression was an independent risk factor for poor DFS (P < 0.001) and OS (P < 0.001) in all eligible patients. Of 100 patients who received neoadjuvant chemotherapy (NAC), high ADAM12 expression was significantly associated with poor DFS in a subset of patients treated with the nab-paclitaxel (PTX) neoadjuvant regimen (P = 0.03), whereas the prognostic value of ADAM12 was not evident in patients not treated with nab-PTX (P = 0.12). CONCLUSIONS: A negative prognostic value of high ADAM12 expression was observed in patients with PDAC treated with surgical resection, which was enhanced in patients treated with NAC, including nab-PTX. These results suggested that ADAM12 expression can predict nab-PTX chemosensitivity in PDAC and reflect PDAC progression.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Proteína ADAM12 , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/cirugía , Desoxicitidina/uso terapéutico , Desintegrinas/uso terapéutico , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , Pronóstico , Estudios Retrospectivos , Neoplasias PancreáticasRESUMEN
Snake venoms are a potential source of various enzymatic and non-enzymatic compounds with a defensive role for the host. Various peptides with significant medicinal properties have been isolated and characterized from these venoms. Few of these are FDA approved. They inhibit tumor cells adhesion, migration, angiogenesis and metastasis by inhibiting integrins on transmembrane cellular surfaces. This plays important role in delaying tumor growth, neovascularization and development. Tumor targeting and smaller size make them ideal candidates as novel therapeutic agents for cancer treatment. This review is based on sources of these disintegrins, their targeting modality, classification and underlying anti-cancer potential.
Asunto(s)
Antineoplásicos/uso terapéutico , Desintegrinas/uso terapéutico , Integrinas/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Venenos de Serpiente/metabolismo , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/aislamiento & purificación , Desintegrinas/efectos adversos , Desintegrinas/aislamiento & purificación , Humanos , Integrinas/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Transducción de SeñalRESUMEN
Snake venoms consist of a complex mixture of many bioactive molecules. Among them are disintegrins, which are peptides without enzymatic activity, but with high binding affinity for integrins, transmembrane receptors that function to connect cells with components of the extracellular matrix. Integrin-mediated cell attachment is critical for cell migration and dissemination, as well as for signal transduction pathways involved in cell growth. During tumor development, integrins play key roles by supporting cancer cell proliferation, angiogenesis, and metastasis. The recognition that snake venom disintegrins can block integrin functions has spawned a number of studies to explore their cancer therapeutic potential. While dozens of different disintegrins have been isolated, none of them as yet has undergone clinical evaluation in cancer patients. Among the best-characterized and preclinically most advanced disintegrins is vicrostatin (VCN), a recombinant disintegrin that was rationally designed by fusing 62 N-terminal amino acids derived from the disintegrin contortrostatin with 6 C-terminal amino acids from echistatin, the disintegrins from another snake species. Bacterially produced VCN was shown to target multiple tumor-associated integrins, achieving potent anti-tumor and anti-angiogenic effects in in vitro and in vivo models in the absence of noticeable toxicity. This review will introduce the field of snake venom disintegrins as potential anticancer agents and illustrate the translational development and cancer-therapeutic potential of VCN as an example.
Asunto(s)
Antineoplásicos/farmacología , Desintegrinas/farmacología , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Desintegrinas/química , Desintegrinas/uso terapéutico , Evaluación Preclínica de Medicamentos/métodos , Humanos , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/uso terapéutico , Venenos de Serpiente/química , Venenos de Serpiente/metabolismoRESUMEN
Hemorrhagic transformation after ischemic stroke is an independent predictor for poor outcome and is characterized by blood vessel rupture leading to brain edema. To date, no therapies for preventing hemorrhagic transformation exist. Disintegrins from the venom of Crotalus atrox have targets within the coagulation cascade, including receptors on platelets. We hypothesized that disintegrins from C. atrox venom can attenuate hemorrhagic transformation by preventing activation of matrix metalloproteinase after middle cerebral artery occlusion (MCAO) in hyperglycemic rats. We subjected 48 male Sprague-Dawley rats weighing 240-260 g to MCAO and hyperglycemia to induce hemorrhagic transformation of the infarction. At reperfusion, we administered either saline (vehicle), whole C. atrox venom (two doses were used), or fractionated C. atrox venom (HPLC Fraction 2). Rats were euthanized 24 hr post-ictus for measurement of infarction and hemoglobin volume. Reversed-phase HPLC was performed to fractionate the whole venom and peaks were combined to form Fraction 2, which contained the disintegrin Crotatroxin. Fraction 2 protected against hemorrhagic transformation after MCAO, and attenuated activation of matrix metalloproteinase-9. Administering matrix metalloproteinase antagonists prevented the protection by Fraction 2. The results of this study indicate that disintegrins found in C. atrox venom may have therapeutic potential for reducing hemorrhagic transformation after ischemic stroke. Moreover, the RP-HPLC fractions retained sufficient protein activity to suggest that gentler and less efficient orthogonal chromatographic methods may be unnecessary to isolate proteins and explore their function.
Asunto(s)
Desintegrinas/farmacología , Hiperglucemia/complicaciones , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Hemorragias Intracraneales/prevención & control , Metaloproteinasa 9 de la Matriz/metabolismo , Inhibidores de Agregación Plaquetaria/farmacología , Animales , Modelos Animales de Enfermedad , Desintegrinas/uso terapéutico , Hiperglucemia/metabolismo , Hiperglucemia/patología , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Hemorragias Intracraneales/etiología , Hemorragias Intracraneales/metabolismo , Hemorragias Intracraneales/patología , Masculino , Inhibidores de Agregación Plaquetaria/uso terapéutico , Ratas , Ratas Sprague-DawleyRESUMEN
A disintegrin and metalloproteinase (ADAM)12 is considered to promote cardiac dysfunction based on the finding that a small-molecule ADAM12 inhibitor, KB-R7785, ameliorated cardiac function in a transverse aortic constriction (TAC) model by inhibiting the proteolytic activation of heparin-binding-EGF signaling. However, this compound has poor selectivity for ADAM12, and the role of ADAM12 in cardiac dysfunction has not yet been investigated using genetic loss-of-function mice. We revealed that ADAM12 knockout mice showed significantly more advanced cardiac hypertrophy and higher mortality rates than wild-type mice 4 wk after TAC surgery. An ADAM12 deficiency resulted in significantly more expanded cardiac fibrosis accompanied by increased collagen-related gene expression in failing hearts. The results of a genome-wide transcriptional analysis suggested a strongly enhanced focal adhesion- and fibrosis-related signaling pathway in ADAM12 knockout hearts. The loss of ADAM12 increased the abundance of the integrinß1 subunit and transforming growth factor (TGF)-ß receptor types I and III, and this was followed by the phosphorylation of focal adhesion kinase, Akt, mammalian target of rapamycin, ERK, and Smad2/3 in the heart, which resulted in cardiac dysfunction. The present results revealed that the loss of ADAM12 enhanced focal adhesion and canonical TGF-ß signaling by regulating the abundance of the integrinß1 and TGF-ß receptors.NEW & NOTEWORTHY In contrast to a long-believed cardio-damaging role of a disintegrin and metalloproteinase (ADAM)12, cardiac hypertrophy was more severe, cardiac function was lower, and mortality was higher in ADAM12 knockout mice than in wild-type mice after transverse aortic constriction surgery. The loss of ADAM12 enhanced focal adhesion- and fibrosis-related signaling pathways in the heart, which may compromise cardiac function. These results provide insights for the development of novel therapeutics that target ADAM12 to treat heart failure.
Asunto(s)
Proteína ADAM12/genética , Cardiomegalia/prevención & control , Desintegrinas/uso terapéutico , Insuficiencia Cardíaca/prevención & control , Miocardio/patología , Proteína ADAM12/antagonistas & inhibidores , Proteína ADAM12/efectos de los fármacos , Animales , Presión Sanguínea , Fibrosis , Adhesiones Focales/efectos de los fármacos , Integrina beta1/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Factores de Crecimiento Transformadores beta/efectos de los fármacos , Receptores de Factores de Crecimiento Transformadores beta/genética , Transducción de Señal/efectos de los fármacosRESUMEN
Snake venoms affect blood coagulation and platelet function in diverse ways. Some venom components inhibit platelet function, while other components induce platelet aggregation. Among the platelet aggregation inhibitors, disintegrins have been recognized as unique and potentially valuable tools for examining cell-matrix and cell-cell interactions and for the development of antithrombotic and antiangiogenic agents according to their anti-adhesive and anti-migration effect on tumor cells and antiangiogenesis activities. Disintegrins represent a family of low molecular weight, cysteine-rich, Arg-Gly-Asp(RGD)/Lys-Gly-Asp(KGD)-containing polypeptides, which inhibit fibrinogen binding to integrin αIIbß3 (i.e., platelet glycoprotein IIb/IIIa), as well as ligand binding to integrins αvß3, and α5ß1 expressed on cells (i.e., fibroblasts, tumor cells, and endothelial cells). This review focuses on the current efforts attained from studies using disintegrins as a tool in the field of arterial thrombosis, angiogenesis, inflammation, and tumor metastasis, and briefly describes their potential therapeutic applications and side effects in integrin-related diseases. Additionally, novel R(K)GD-containing disintegrin TMV-7 mutants are being designed as safer antithrombotics without causing thrombocytopenia and bleeding.
Asunto(s)
Desintegrinas/uso terapéutico , Fibrinolíticos/uso terapéutico , Venenos de Serpiente/química , Animales , Antiinflamatorios/uso terapéutico , Antineoplásicos/uso terapéutico , Humanos , Integrinas/antagonistas & inhibidores , Inhibidores de Agregación Plaquetaria/uso terapéuticoRESUMEN
Leucurogin is an ECD disintegrin-like protein, cloned from Bothrops leucurus venom gland. This new protein, encompassing the disintegrin region of a PIII metalloproteinase, is produced by recombinant technology and its biological and functional activity was partially characterized in this study. Biological activity was characterized in vitro using human fibroblasts. Functional activity of leucurogin was analysed in vitro and in vivo with murine B16F10 Nex-2 and human melanoma BLM cells. The results show that leucurogin inhibits cellular processes dependent on collagen type I. In a competition assay with collagen, leucurogin inhibits, in a dose-dependent manner, the adhesion of fibroblast to collagen. At 10⯵M leucurogin reduces adhesion (40%) and migration (70%) of hFb and inhibits migration (32%) and proliferation (65%) of BLM cells. At 2.5⯵M leucurogin inhibits 80% cell proliferation of B16F10 Nex-2 melanoma cells. At 4.8⯵M leucurogin inhibits, in vitro, the vascular structures formation by endothelial cells by 66%. Leucurogin, injected intraperitoneally, i.p. (5 µg/animal, two-month old C57/Bl6 male mice) on alternate days for 15 days, inhibits lung metastasis of B16F10 Nex-2â¯cells by 70-75%. In the treatment of human melanoma, grafted intradermally in the nude mice flank, leucurogin (7.5⯵g/kg in alternate days during 17 days) inhibits tumor growth by more than 40%. Leucurogin can be considered a promising agent for melanoma treatment.
Asunto(s)
Venenos de Crotálidos/química , Desintegrinas/uso terapéutico , Melanoma/tratamiento farmacológico , Proteínas Recombinantes/uso terapéutico , Animales , Bothrops/metabolismo , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Desintegrinas/química , Desintegrinas/aislamiento & purificación , Fibroblastos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Masculino , Melanoma/patología , Metaloproteasas/química , Metaloproteasas/aislamiento & purificación , Ratones , Proteínas Recombinantes/químicaRESUMEN
Alternagin-C (ALT-C) is a disintegrin-like peptide purified from Rhinocerophis alternatus snake venom with the property of inducing vascular endothelial growth factor (VEGF) expression, endothelial cell proliferation and migration, and angiogenesis. Therefore, this protein could be interesting as a new approach for ischemic heart diseases, an imbalance between myocardial oxygen supply and demand, leading to cardiac dysfunction. We investigated the effects of a single dose of alternagin-C (0.5â¯mgâ¯kg-1, via intra-arterial), after 7â¯days, on hypoxia/reoxygenation challenge in isolated ventricle strips and on morphological changes and density of blood vessels of the heart, using fish as an alternative experimental model. ALT-C treatment provided protection of cardiomyocytes against hypoxia/reoxygenation-induced negative inotropism. ALT-C also stimulated angiogenesis and improved excitation-contraction coupling during hypoxic conditions. Our results provide a new insight into a functional role of ALT-C against hypoxia/reoxygenation-induced cardiomyocyte injury pointing out to a potential therapeutic strategy for ischemia-related diseases.
Asunto(s)
Bothrops , Cardiotónicos/uso terapéutico , Venenos de Crotálidos/química , Modelos Animales de Enfermedad , Desintegrinas/uso terapéutico , Daño por Reperfusión Miocárdica/prevención & control , Proteínas de Reptiles/uso terapéutico , Inductores de la Angiogénesis/administración & dosificación , Inductores de la Angiogénesis/uso terapéutico , Animales , Acuicultura , Cardiotónicos/administración & dosificación , Characiformes , Colágeno/metabolismo , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/patología , Vasos Coronarios/fisiopatología , Desintegrinas/administración & dosificación , Acoplamiento Excitación-Contracción/efectos de los fármacos , Proteínas de Peces/metabolismo , Corazón/efectos de los fármacos , Corazón/fisiología , Corazón/fisiopatología , Inyecciones Intraarteriales , Contracción Miocárdica/efectos de los fármacos , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Miocardio/metabolismo , Miocardio/patología , Neovascularización Fisiológica/efectos de los fármacos , Proteínas de Reptiles/administración & dosificaciónRESUMEN
Integrins are heterodimeric cell surface receptors that mediate cell-cell and cell-matrix interaction. The vitronectin and osteopontin receptor αvß3 integrin has increased expression levels and is implicated in the adhesion, activation, and migration of osteoclasts on the bone surface as well as osteoclast polarization. αvß3 integrin plays an important role in osteoclast differentiation and resorption. In addition, Arg-Gly-Asp (RGD)-containing peptides, small molecular inhibitors, and antibodies to αvß3 integrin have been shown to inhibit bone resorption in vitro and in vivo. Here we examined the effects of a disintegrin HSA-ARLDDL a genetically modified mutant of rhodostomin conjugated with human serum albumin, which is highly selective of αvß3, on RANKL-induced osteoclastogenesis and ovariectomy (OVX)-induced osteoporosis. In RANKL-induced osteoclastogenesis, HSA-ARLDDL significantly inhibited osteoclast formation, and IC50 was at nM range. Post-treatment HSA-ARLDDL also inhibits osteoclast formation. Furthermore, weekly administration of HSA-ARLDDL significantly inhibits the increase in serum bone resorption marker levels and decrease in cancellous bone loss in tibia and femur induced by OVX. On the other hand, HSA-ARLDDL did not affect the differentiation and calcium deposition of osteoblasts. These results indicate that the highly selective and long-acting αvß3 integrin antagonists could be developed as effective drugs for postmenopausal osteoporosis.
Asunto(s)
Desintegrinas/farmacología , Integrina alfaVbeta3/antagonistas & inhibidores , Mutación , Osteoporosis/tratamiento farmacológico , Péptidos/genética , Animales , Desintegrinas/química , Desintegrinas/metabolismo , Desintegrinas/uso terapéutico , Femenino , Humanos , Masculino , Ratones , Oligopéptidos/química , Péptidos/metabolismo , Dominios Proteicos , Ratas , Albúmina Sérica/metabolismoRESUMEN
INTRODUCTION: The applicability of protein drugs is confined by protein degradation and rapid elimination. PEGylation of polypeptides improves protein stability by sterically obstructing the degradation by serum proteases and reduces renal clearance by the increased mass. EXPERIMENTAL APPROACH: We compared the antithrombotic activities of intact rhodostomin (Rn) and PEGylated rhodostomin (PRn) both in vitro and in vivo systems. In addition, the functional half-life in inhibiting platelet aggregation and the tendency in causing bleeding side effect were investigated. RESULTS: Rn and PRn both potently inhibited human and mouse platelet aggregation induced by collagen, thrombin or ADP in vitro with a similar IC50 around 60-100nM. Rotational thromboelastometry assay indicated that PRn was more effective than Rn in preventing clot formation in human whole blood. In platelet-rich plasma from mice injected with Rn or PRn, the inhibitory effects on collagen-induced platelet aggregation were also comparable, but Rn caused higher bleeding tendency. In ferric chloride-induced arterial thrombosis, Rn and PRn significantly prolonged occlusion time at high dosage (0.2µg/g). However, PRn obviously prolonged the occlusion time even given at a lower dosage (0.06µg/g). The functional half-life assay revealed that PEGylation prolonged the in vivo half-life of Rn. CONCLUSIONS: PRn exhibits higher antithrombotic potency and longer half-life in vivo as compared with native Rn on a molar basis. In addition, PRn exhibits a better safety profile at an efficacious antithrombotic dose in vivo. Therefore, PEGylation may be one of the ideal options in modifying disintegrin derivatives as the safe therapeutic agents for integrin-related diseases.
Asunto(s)
Hemorragia/inducido químicamente , Péptidos/efectos adversos , Péptidos/uso terapéutico , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Trombosis/tratamiento farmacológico , Animales , Plaquetas/efectos de los fármacos , Desintegrinas/efectos adversos , Desintegrinas/química , Desintegrinas/farmacocinética , Desintegrinas/uso terapéutico , Estabilidad de Medicamentos , Semivida , Hemorragia/sangre , Humanos , Masculino , Ratones , Ratones Endogámicos ICR , Péptidos/química , Péptidos/farmacocinética , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacocinética , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/metabolismo , Polietilenglicoles/química , Estabilidad Proteica , Trombosis/sangreRESUMEN
Adinbitor is a disintegrin previously obtained from Agkistrodon halys brevicaudus stejneger by our group. Here, we investigated the in vitro and in vivo anti-tumor activities of recombinant Adinbitor (rAdinbitor). rAdinbitor stimulation can inhibit the in vitro proliferation, migration and invasion capacities of murine hepatocarcinoma H22 and Hca-F cells. The administrations of rAdinbitor either by gavage or intraperitoneal injection suppress the tumor malignancy and prolong the survival rate and time of H22-transplanted mice. The number and size of formed blood vessels decreased dramatically in tumorous tissues in that the expression levels of vascular endothelial growth factor (VEGF) and cluster of differentiation 34 (CD34) were significantly decreased in responding to rAdinbitor treatment. The protein levels of IL-18 and IgG increased significantly in the serum of H22-transplanted tumor mice with rAdinbitor treatment. rAdinbitor shows in vitro and in vivo anti-tumor effects as an angiogenesis inhibitor and immunocompetence enhancer.
Asunto(s)
Agkistrodon/metabolismo , Desintegrinas/farmacología , Desintegrinas/uso terapéutico , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Desintegrinas/química , Inmunocompetencia , Neoplasias Hepáticas/tratamiento farmacológico , RatonesRESUMEN
Integrins regulate diverse functions in cancer pathology and in tumor cell development and contribute to important processes such as cell shape, survival, proliferation, transcription, angiogenesis, migration, and invasion. A number of snake venom proteins have the ability to interact with integrins. Among these are the disintegrins, a family of small, non-enzymatic, and cysteine-rich proteins found in the venom of numerous snake families. The venom proteins may have a potential role in terms of novel therapeutic leads for cancer treatment. Disintegrin can target specific integrins and as such it is conceivable that they could interfere in important processes involved in carcinogenesis, tumor growth, invasion and migration. Herein we present a survey of studies involving the use of snake venom disintegrins for cancer detection and treatment. The aim of this review is to highlight the relationship of integrins with cancer and to present examples as to how certain disintegrins can detect and affect biological processes related to cancer. This in turn will illustrate the great potential of these molecules for cancer research. Furthermore, we also outline several new approaches being created to address problems commonly associated with the clinical application of peptide-based drugs such as instability, immunogenicity, and availability.
Asunto(s)
Desintegrinas/metabolismo , Desintegrinas/farmacología , Venenos de Serpiente/metabolismo , Animales , Transformación Celular Neoplásica , Progresión de la Enfermedad , Desintegrinas/química , Desintegrinas/uso terapéutico , Descubrimiento de Drogas , Humanos , Integrinas/metabolismo , Ligandos , Imagen Molecular/métodos , Neoplasias/diagnóstico , Neoplasias/etiología , Neoplasias/metabolismo , Neoplasias/patología , Unión ProteicaRESUMEN
Cancer can develop to the extent tumor cells grow, divide and grow into other body tissues. Integrins are a family of cell-surface heterodimeric receptors that play an important role in the development of tumor angiogenesis, growth and metastasis, thus being recognized as an attractive therapeutic target. Snake venom contains low-molecular weight peptides known as "disintegrins" that bind to integrins with high affinity, and prevent their action in cancer. In the next article, we go over the results of investigations, both in vitro and in vivo, which have shown promising results, thus revealing that the use of disintegrins could be a promising alternative for the treatment of different neoplasias.
Asunto(s)
Desintegrinas/farmacología , Desintegrinas/uso terapéutico , Integrinas/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Venenos de Serpiente , Desintegrinas/análisis , Humanos , Integrinas/fisiología , Neoplasias/etiología , Neovascularización Patológica , Venenos de Serpiente/químicaRESUMEN
El desarrollo del cáncer es posible en la medida que las células tumorales proliferen, se dispersen e invadan otros tejidos del cuerpo. Las integrinas son una familia de receptores heterodiméricos de superficie celular que cumplen un papel crucial en el desarrollo de la angiogénesis, crecimiento y metástasis de un tumor señalándolas como un atractivo blanco terapéutico. Los venenos de serpientes contienen péptidos de bajo peso molecular conocidos como desintegrinas, las que se unen con una alta afinidad a las integrinas e inhiben su accionar en un proceso cancerígeno. En el siguiente articulo revisamos los resultados de investigaciones, tanto in vitro como in vivo, que han mostrado resultados promisorios, por lo cual el uso de las desintegrinas podrían constituir una alternativa promisoria para el tratamiento de diversas neoplasias.
Cancer can develop to the extent tumor cells grow, divide and grow into other body tissues. Integrins are a family of cell-surface heterodimeric receptors that play an important role in the development of tumor angiogenesis, growth and metastasis, thus being recognized as an attractive therapeutic target. Snake venom contains low-molecular weight peptides known as disintegrins that bind to integrins with high affinity, and prevent their action in cancer. In the next article, we go over the results of investigations, both in vitro and in vivo, which have shown promising results, thus revealing that the use of disintegrins could be a promising alternative for the treatment of different neoplasias.
Asunto(s)
Humanos , Desintegrinas/farmacología , Desintegrinas/uso terapéutico , Integrinas/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Venenos de Serpiente , Desintegrinas/análisis , Integrinas/fisiología , Neoplasias/etiología , Neovascularización Patológica , Venenos de Serpiente/químicaRESUMEN
BACKGROUND: There are few available treatments for hormone refractory prostate cancer. Through the inhibition of integrins, contortrostatin (CN) effects tumor cell growth directly as well as through the inhibition of angiogenesis. The effect of CN in combination with docetaxel on prostate cancer cell lines in vitro and in vivo is evaluated in the present study. METHODS: FACS analysis of integrin expression, assessment of CN and docetaxel exposure on viability of plated cancer cells, and scratch test migration analysis were performed on PC-3 prostate cancer cells. CN and docetaxel inhibition of both PC-3 and CWR-22 prostate cancer cell lines were evaluated in a mouse xenograft bone model. Angiogenic activity in tumors were assessed using IHC with antibodies to CD31. RESULTS: Cell culture experiments indicate that the combination of docetaxel and CN inhibits growth in an additive fashion. FACS analysis of PC-3 cells shows expression of alpha5beta1 and alphavbeta5 integrins, but little expression of the alphavbeta3. CN showed complete inhibition of PC-3 migration in cultures grown on matrigel plates. In mice xenograft bone models, CN with docetaxel showed increased inhibition of both PC-3 and CWR-22 derived tumors. Analysis of treated xenograft tumors showed significantly decreased expression of CD31 indicating suppression of angiogenesis.
Asunto(s)
Desintegrinas/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Taxoides/uso terapéutico , Animales , Neoplasias Óseas/prevención & control , Neoplasias Óseas/secundario , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Docetaxel , Humanos , Masculino , Ratones , Trasplante de Neoplasias , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/prevención & control , Neoplasias de la Próstata/patología , Trasplante Heterólogo , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
Few of the proteins isolated and characterized from snake venom have proven to be more chemically diverse, exquisitely specific or promiscuously active than the family known as disintegrins. These small proteins have shown structural homology with hundreds of cell surface molecules from plants and animals other than snakes, and their precise mimicry of native receptor ligands speaks to evolutionary niches related to survival and geographic locale. Over 100 disintegrins have been named and studied, with the most recent efforts into molecular techniques providing significant clues to taxonomic relationships among four different snake families. Investigators have evaluated disintegrin applications in therapies for cancer, asthma, osteopenia and inappropriate angiogenesis. Crystal and NMR studies have confirmed hypotheses regarding ligand-receptor interactions while illuminating the complexities of structure-function evidence. Disintegrin chimeras with viruses, microbubbles and fluorescent labels have become useful tools in many investigations. While many disintegrin studies still involve platelets, previously unexplored interactions with glial cancer, T lymphocytes and the bacteria Yersinia have blazed new trails for this field. This review will summarize disintegrin investigations since 2003.
Asunto(s)
Enfermedad , Desintegrinas/fisiología , Animales , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Cristalografía , Desintegrinas/química , Desintegrinas/genética , Desintegrinas/uso terapéutico , Salud , Humanos , Leucocitos/efectos de los fármacos , Leucocitos/fisiología , Espectroscopía de Resonancia Magnética , Modelos Animales , Neoplasias/tratamiento farmacológicoRESUMEN
Angiogenesis is the fundamental process by which new blood vessels are formed. Extensive research has shown that this event can be co-opted by tumors to ensure their growth, survival and metastasis. The study of tumor angiogenesis therefore represents a promising area of research for development of anti-cancer therapeutics. Integrins, a family of cell surface molecules, are a major target of interest as they are known to play a vital role in pathological angiogenesis. Remarkably, small disulfide-rich peptides known as disintegrins, isolated from the venoms of various snake species have been found to bind integrins with extremely high affinity and block their function. Disintegrins are capable of inhibiting several aspects of tumor cell behavior both in vitro and in vivo, including adhesion, migration, invasion, metastasis and angiogenesis. In this review, we will briefly discuss tumor angiogenesis and molecules implicated in the angiogenic process, with a special focus on the role of integrins. We will also discuss therapeutic approaches towards the treatment of tumor angiogenesis, including non-integrin-targeted agents currently in clinical trials. We will summarize the major findings from studies using disintegrins to target integrin-associated angiogenesis in cancer models. Finally, we will present results obtained in our laboratory using the novel dimeric disintegrin, contortrostatin (CN), in studies of endothelial cells and models of breast, ovarian and prostate cancer. In summary, disintegrins represent an exciting new class of molecules that can potentially be used in a clinical setting to inhibit angiogenesis and augment conventional chemotherapeutic agents in the treatment of cancer.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Desintegrinas/uso terapéutico , Oligopéptidos/uso terapéutico , Venenos de Serpiente/uso terapéutico , Animales , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismoRESUMEN
OBJECTIVES: To investigate the independent and combined effects of lifestyle changes and statin treatment on soluble markers of atherosclerotic activity. DESIGN: The study was a randomised, 2 x 2 factorial 1 year intervention trial. Participants (n=177) were sedentary, drug-treated, hypertensive men (aged 40-74 years). They were randomised to placebo, lifestyle intervention (diet and physical activity), fluvastatin 40 mg, or the combination of lifestyle and fluvastatin. RESULTS: Lifestyle intervention significantly reduced intercellular adhesion molecule-1 (sICAM-1) compared to usual care (p=0.003). Thrombomodulin level remained higher among individuals receiving lifestyle intervention (p=0.025). sICAM-1 was less reduced among fluvastatin treated participants compared to the placebo treated (p=0.029). Changes of blood pressure, weight or waist circumference were not significantly different between treatment groups. Individuals who achieved improvement of classical risk factors also had a significant reduction of endothelial markers (E-selectin, von Willebrands factor, tissue plasminogen activator antigen). CONCLUSIONS: One year of lifestyle intervention reduced the level of sICAM-1 in sedentary, drug-treated hypertensives, in spite of no impact on traditional risk factors. Low dose fluvastatin had no beneficial effect on the measured markers.
Asunto(s)
Arteriosclerosis/tratamiento farmacológico , Desintegrinas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Hipertensión/tratamiento farmacológico , Estilo de Vida , Adulto , Anciano , Arteriosclerosis/diagnóstico , Biomarcadores , Desintegrinas/uso terapéutico , Endotelinas/efectos de los fármacos , Femenino , Hemostasis/efectos de los fármacos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipertensión/diagnóstico , Inflamación , Molécula 1 de Adhesión Intercelular , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
ADAM10 is a disintegrin metalloproteinase that processes amyloid precursor protein and ErbB ligands and is involved in the shedding of many type I and type II single membrane-spanning proteins. Like tumor necrosis factor-alpha-converting enzyme (TACE or ADAM17), ADAM10 is expressed as a zymogen, and removal of the prodomain results in its activation. Here we report that the recombinant mouse ADAM10 prodomain, purified from Escherichia coli, is a potent competitive inhibitor of the human ADAM10 catalytic/disintegrin domain, with a K(i) of 48 nM. Moreover, the mouse ADAM10 prodomain is a selective inhibitor as it only weakly inhibits other ADAM family proteinases in the micromolar range and does not inhibit members of the matrix metalloproteinase family under similar conditions. Mouse prodomains of TACE and ADAM8 do not inhibit their respective enzymes, indicating that ADAM10 inhibition by its prodomain is unique. In cell-based assays we show that the ADAM10 prodomain inhibits betacellulin shedding, demonstrating that it could be of potential use as a therapeutic agent to treat cancer.