Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 14 de 14
Filtrar
1.
Am J Hum Genet ; 105(3): 625-630, 2019 09 05.
Artículo en Inglés | MEDLINE | ID: mdl-31303264

RESUMEN

Rothmund-Thomson syndrome (RTS) is an autosomal-recessive disorder characterized by poikiloderma, sparse hair, short stature, and skeletal anomalies. Type 2 RTS, which is defined by the presence of bi-allelic mutations in RECQL4, is characterized by increased cancer susceptibility and skeletal anomalies, whereas the genetic basis of RTS type 1, which is associated with juvenile cataracts, is unknown. We studied ten individuals, from seven families, who had RTS type 1 and identified a deep intronic splicing mutation of the ANAPC1 gene, a component of the anaphase-promoting complex/cyclosome (APC/C), in all affected individuals, either in the homozygous state or in trans with another mutation. Fibroblast studies showed that the intronic mutation causes the activation of a 95 bp pseudoexon, leading to mRNAs with premature termination codons and nonsense-mediated decay, decreased ANAPC1 protein levels, and prolongation of interphase. Interestingly, mice that were heterozygous for a knockout mutation have an increased incidence of cataracts. Our results demonstrate that deficiency in the APC/C is a cause of RTS type 1 and suggest a possible link between the APC/C and RECQL4 helicase because both proteins are involved in DNA repair and replication.


Asunto(s)
Ciclosoma-Complejo Promotor de la Anafase/genética , Subunidad Apc1 del Ciclosoma-Complejo Promotor de la Anafase/genética , Mutación , Síndrome Rothmund-Thomson/genética , Humanos
2.
Genet Med ; 23(1): 149-154, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32873933

RESUMEN

PURPOSE: Biallelic variants in TBC1D24, which encodes a protein that regulates vesicular transport, are frequently identified in patients with DOORS (deafness, onychodystrophy, osteodystrophy, intellectual disability [previously referred to as mental retardation], and seizures) syndrome. The aim of the study was to identify a genetic cause in families with DOORS syndrome and without a TBC1D24 variant. METHODS: Exome or Sanger sequencing was performed in individuals with a clinical diagnosis of DOORS syndrome without TBC1D24 variants. RESULTS: We identified the same truncating variant in ATP6V1B2 (NM_001693.4:c.1516C>T; p.Arg506*) in nine individuals from eight unrelated families with DOORS syndrome. This variant was already reported in individuals with dominant deafness onychodystrophy (DDOD) syndrome. Deafness was present in all individuals, along with onychodystrophy and abnormal fingers and/or toes. All families but one had developmental delay or intellectual disability and five individuals had epilepsy. We also describe two additional families with DDOD syndrome in whom the same variant was found. CONCLUSION: We expand the phenotype associated with ATP6V1B2 and propose another causal gene for DOORS syndrome. This finding suggests that DDOD and DOORS syndromes might lie on a spectrum of clinically and molecularly related conditions.


Asunto(s)
Epilepsia , Discapacidad Intelectual , Uñas Malformadas , ATPasas de Translocación de Protón Vacuolares , Epilepsia/genética , Exoma , Proteínas Activadoras de GTPasa , Humanos , Discapacidad Intelectual/genética , Uñas Malformadas/genética , Fenotipo , ATPasas de Translocación de Protón Vacuolares/genética
3.
Am J Hum Genet ; 101(5): 856-865, 2017 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-29100095

RESUMEN

Approximately one in every 200 mammalian proteins is anchored to the cell membrane through a glycosylphosphatidylinositol (GPI) anchor. These proteins play important roles notably in neurological development and function. To date, more than 20 genes have been implicated in the biogenesis of GPI-anchored proteins. GPAA1 (glycosylphosphatidylinositol anchor attachment 1) is an essential component of the transamidase complex along with PIGK, PIGS, PIGT, and PIGU (phosphatidylinositol-glycan biosynthesis classes K, S, T, and U, respectively). This complex orchestrates the attachment of the GPI anchor to the C terminus of precursor proteins in the endoplasmic reticulum. Here, we report bi-allelic mutations in GPAA1 in ten individuals from five families. Using whole-exome sequencing, we identified two frameshift mutations (c.981_993del [p.Gln327Hisfs∗102] and c.920delG [p.Gly307Alafs∗11]), one intronic splicing mutation (c.1164+5C>T), and six missense mutations (c.152C>T [p.Ser51Leu], c.160_161delinsAA [p.Ala54Asn], c.527G>C [p.Trp176Ser], c.869T>C [p.Leu290Pro], c.872T>C [p.Leu291Pro], and c.1165G>C [p.Ala389Pro]). Most individuals presented with global developmental delay, hypotonia, early-onset seizures, cerebellar atrophy, and osteopenia. The splicing mutation was found to decrease GPAA1 mRNA. Moreover, flow-cytometry analysis of five available individual samples showed that several GPI-anchored proteins had decreased cell-surface abundance in leukocytes (FLAER, CD16, and CD59) or fibroblasts (CD73 and CD109). Transduction of fibroblasts with a lentivirus encoding the wild-type protein partially rescued the deficiency of GPI-anchored proteins. These findings highlight the role of the transamidase complex in the development and function of the cerebellum and the skeletal system.


Asunto(s)
Aciltransferasas/genética , Atrofia/genética , Enfermedades Óseas Metabólicas/genética , Discapacidades del Desarrollo/genética , Epilepsia/genética , Glicoproteínas de Membrana/genética , Mutación/genética , Adolescente , Adulto , Alelos , Cerebelo/patología , Niño , Preescolar , Exoma/genética , Femenino , Fibroblastos/patología , Glicosilfosfatidilinositoles/genética , Humanos , Masculino , Hipotonía Muscular/genética , Linaje , ARN Mensajero/genética , Convulsiones/genética
4.
Am J Hum Genet ; 100(1): 91-104, 2017 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-27939640

RESUMEN

Identification of over 500 epigenetic regulators in humans raises an interesting question regarding how chromatin dysregulation contributes to different diseases. Bromodomain and PHD finger-containing protein 1 (BRPF1) is a multivalent chromatin regulator possessing three histone-binding domains, one non-specific DNA-binding module, and several motifs for interacting with and activating three lysine acetyltransferases. Genetic analyses of fish brpf1 and mouse Brpf1 have uncovered an important role in skeletal, hematopoietic, and brain development, but it remains unclear how BRPF1 is linked to human development and disease. Here, we describe an intellectual disability disorder in ten individuals with inherited or de novo monoallelic BRPF1 mutations. Symptoms include infantile hypotonia, global developmental delay, intellectual disability, expressive language impairment, and facial dysmorphisms. Central nervous system and spinal abnormalities are also seen in some individuals. These clinical features overlap with but are not identical to those reported for persons with KAT6A or KAT6B mutations, suggesting that BRPF1 targets these two acetyltransferases and additional partners in humans. Functional assays showed that the resulting BRPF1 variants are pathogenic and impair acetylation of histone H3 at lysine 23, an abundant but poorly characterized epigenetic mark. We also found a similar deficiency in different lines of Brpf1-knockout mice. These data indicate that aberrations in the chromatin regulator gene BRPF1 cause histone H3 acetylation deficiency and a previously unrecognized intellectual disability syndrome.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Cromatina/metabolismo , Histonas/metabolismo , Discapacidad Intelectual/genética , Mutación , Proteínas Nucleares/genética , Acetilación , Adolescente , Alelos , Animales , Proteínas Portadoras/genética , Niño , Cromatina/química , Proteínas de Unión al ADN , Discapacidades del Desarrollo/genética , Cara/anomalías , Femenino , Histona Acetiltransferasas/genética , Humanos , Lisina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Hipotonía Muscular/genética , Síndrome
6.
Am J Pathol ; 179(1): 462-76, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21703424

RESUMEN

Malignant astrocytomas, the most common primary brain tumors, are predominantly fatal. Improved treatments will require a better understanding of the biological features of high-grade astrocytomas. To better understand the role of neuronal PAS 3 (NPAS3) in diseases in human beings, it was investigated as a candidate for astrocytomagenesis based on the presence of aberrant protein expression in greater than 70% of a human astrocytoma panel (n = 433) and most notably in surgically resected malignant lesions. In subsequent functional studies, it was concluded that NPAS3 exhibits features of a tumor-suppressor, which drives the progression of astrocytomas by modulating the cell cycle, proliferation, apoptosis, and cell migration/invasion and has a further influence on the viability of endothelial cells. Of clinical importance, absence of NPAS3 expression in glioblastomas was a significantly negative prognostic marker of survival. In addition, malignant astrocytomas lacking NPAS3 expression demonstrated loss of function mutations, which were associated with loss of heterozygosity. While overexpressed NPAS3 in malignant glioma cell lines significantly suppressed transformation, the converse decreased expression considerably induced more aggressive growth. In addition, knockdown NPAS3 expression in a human astrocyte cell line in concert with the human papillomavirus E6 and E7 oncogenes induced growth of malignant astrocytomas. In conclusion, NPAS3 drives the progression of human malignant astrocytomas as a tumor suppressor and is a negative prognostication marker for survival.


Asunto(s)
Astrocitoma/genética , Astrocitoma/patología , Transformación Celular Neoplásica , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Animales , Apoptosis , Astrocitoma/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Western Blotting , Encéfalo/metabolismo , Encéfalo/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Adhesión Celular , Ciclo Celular , Movimiento Celular , Proliferación Celular , Células Cultivadas , Metilación de ADN , Endotelio Vascular/citología , Endotelio Vascular/metabolismo , Técnica del Anticuerpo Fluorescente , Humanos , Técnicas para Inmunoenzimas , Pérdida de Heterocigocidad , Ratones , Ratones Endogámicos NOD , Ratones SCID , Mutación/genética , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de Supervivencia , Proteínas Supresoras de Tumor
7.
Clin Invest Med ; 35(5): E246, 2012 Oct 06.
Artículo en Inglés | MEDLINE | ID: mdl-23043706

RESUMEN

PURPOSE: To present an assortment of molecular targets evident from a variety of signal transduction pathways and downstream effectors, which may have clinical relevance for the treatment of medulloblastomas. SOURCE: Data were archived from MEDLINE, using Boolean-formatted queries on the keywords including: medulloblastoma, pathology, prognosis, classification, tumor regression, inhibition, therapy, clinical trial, therapeutic agent, drug, molecular inhibitor, and signalling pathway. Only the most reputable articles were selected for critical analyses based on the qualitative assessment of the citation index, novelty of the findings and relevance to prospective novel ways of targeted therapies for medulloblastomas. PRINCIPAL FINDINGS: Medulloblastomas are highly aggressive embryonal tumors of the cerebellum, akin to primitive neuroectodermal tumors elsewhere in the brain. Current treatments for medulloblastomas which include a combination of surgery, chemotherapy and radiation, remain challenging especially, for younger patients; however, advances in understanding regulatory pathways in medulloblastomas are crucial to develop more effective therapeutic targets. Evidence showing several molecular and pharmacological targets within key signalling pathways, such as HEDGEHOG, WNT, NOTCH, Receptor Tyrosine Kinase (ERB, IGF-IR, c-MET, PDGF, Estrogen, p75NTR) , their downstream effectors like PI3K/AKT, c-MYC and STAT3, and as well as other targets such as telomerase and cytoskeletal elements, is summarized. All molecular and pharmacological targets have pivotal roles in the pathogenesis of medulloblastomas. Most importantly, these pathways can be effectively pharmacologically targeted to regress the growth of medulloblastomas. Pre-clinical studies were routinely undertaken with a variety of human and murine cell lines and as well as murine models of medulloblastomas. Thus far, two drugs which target the NOTCH and HEDGEHOG signalling have completed Phase I clinical trials, but with evidence of low efficacies; hence, reinforcing the importance of continuing investigations in search of new therapeutic agents and targets. CONCLUSION: Novel therapies, based on better understanding key biological pathways in medulloblastomas, hold promise for improved treatments in due course among patients with medulloblastomas.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Cerebelosas/tratamiento farmacológico , Meduloblastoma/tratamiento farmacológico , Antineoplásicos/farmacología , Neoplasias Cerebelosas/metabolismo , Neoplasias Cerebelosas/patología , Cerebelo/metabolismo , Cerebelo/patología , Humanos , Meduloblastoma/metabolismo , Meduloblastoma/patología , Transducción de Señal/efectos de los fármacos
8.
Clin Invest Med ; 33(4): E223-33, 2010 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-20691140

RESUMEN

PURPOSE: To provide a critical assessment of the clinical translational applications of microRNA (miRNA) genes in medulloblastomas. METHODS: Data were obtained from MEDLINE using Boolean-formatted keyword queries. Top articles were selected for critical analyses - depending on the novelty of findings, qualitative assessment of the citation index and relevance to the diagnosis, prognosis and therapeutic targeting of medulloblastomas. RESULTS: MiRNAs, non-protein-coding RNA molecules, negatively regulate gene expression in a sequence-specific manner during biological processes. In the past few years, miRNA genes have emerged as key regulators of not only molecular events involved in normal brain development and function but also in the molecular pathogenesis of medulloblastomas. In this manner, microRNA genes are identified with functional roles as oncogenes and tumor suppressor genes. At least four miRNAs have proven useful in improving the molecular classification of medulloblastomas, and eight others have shown potential in predicting patients' overall prognosis. Moreover, more than 10 miRNA genes can be potentially utilized in therapies against medulloblastomas, using nine recent methods of targetting miRNAs. CONCLUSION: The quest to identify miRNA genes that are of biological significance in medulloblastomas is on an ongoing venture. Most importantly, these miRNAs have been shown to be of clinical importance for improving the accuracy of diagnosis and prognosis and even developing therapies that can significantly improve patients' overall survival from this deadly disease.


Asunto(s)
Meduloblastoma/genética , Meduloblastoma/terapia , MicroARNs/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Meduloblastoma/diagnóstico , Meduloblastoma/metabolismo , MicroARNs/fisiología , Terapia Molecular Dirigida , Pronóstico
9.
Front Neurol ; 11: 767, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32849222

RESUMEN

DOORS [deafness, onychodystrophy, osteodystrophy, intellectual disability (mental retardation), and seizures] syndrome can be caused by mutations in the TBC1D24 and ATP6V1B2 genes, both of which are involved in endolysosomal function. Because of its extreme rarity, to date, no detailed neuropathological assessment has been performed to establish clinicopathological relationships and, thereby, understand better the neurobiology of this disease in aged cases. Accordingly, the aim of the current study was to highlight the clinicopathological characteristics of a novel case with a presumable de novo mutation in the ATP6V1B2 gene from a neuropathological point of view. This Caucasian male patient, who died at the age of 72 years, presented all the typical cardinal signs of DOORS syndrome. In addition, behavioral alterations, pyramidal signs, and Parkinsonism were observed. The p.R506X pathogenic mutation identified in the ATP6V1B2 gene was responsible for the clinical phenotype. The detailed neuropathological assessment revealed a limbic-predominant tauopathy in the forms of argyrophilic grain disease, primary age-related tauopathy, and age-related tau-astrogliopathy. In summary, we present the first detailed clinicopathological report of a patient with DOORS syndrome harboring a pathogenic mutation in the ATP6V1B2 gene. The demonstrated tauopathy may be considered as a consequence of lysosomal and/or mitochondrial dysfunction, similar to that found in Niemann-Pick type C disease, which is another lysosomal disorder characterized by premature neurodegenerative disorder.

10.
Eur J Hum Genet ; 26(3): 340-349, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29330547

RESUMEN

Fryns syndrome (FS) is a multiple malformations syndrome with major features of congenital diaphragmatic hernia, pulmonary hypoplasia, craniofacial dysmorphic features, distal digit hypoplasia, and a range of other lower frequency malformations. FS is typically lethal in the fetal or neonatal period. Inheritance is presumed autosomal recessive. Although no major genetic cause has been identified for FS, biallelic truncating variants in PIGN, encoding a component of the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway, have been identified in a limited number of cases with a phenotype compatible with FS. Biallelic variants in PIGN, typically missense or compound missense with truncating, also cause multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1). Here we report six further patients with FS with or without congenital diaphragmatic hernia and recessive loss of function PIGN alleles, including an intragenic deletion with a likely founder effect in La Réunion and other Indian Ocean islands. Our results support the hypothesis that a spectrum of phenotypic severity is associated with recessive PIGN variants, ranging from FS at the extreme end, caused by complete loss of function, to MCAHS1, in which some residual PIGN function may remain. Our data add FS resulting from PIGN variants to the catalog of inherited GPI deficiencies caused by the disruption of the GPI-anchor biosynthesis pathway.


Asunto(s)
Efecto Fundador , Hernia Diafragmática/genética , Deformidades Congénitas de las Extremidades/genética , Mutación con Pérdida de Función , Fosfotransferasas/genética , Facies , Femenino , Eliminación de Gen , Hernia Diafragmática/patología , Humanos , Lactante , Recién Nacido , Deformidades Congénitas de las Extremidades/patología , Masculino
11.
Neurology ; 87(1): 77-85, 2016 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-27281533

RESUMEN

OBJECTIVE: To evaluate the phenotypic spectrum associated with mutations in TBC1D24. METHODS: We acquired new clinical, EEG, and neuroimaging data of 11 previously unreported and 37 published patients. TBC1D24 mutations, identified through various sequencing methods, can be found online (http://lovd.nl/TBC1D24). RESULTS: Forty-eight patients were included (28 men, 20 women, average age 21 years) from 30 independent families. Eighteen patients (38%) had myoclonic epilepsies. The other patients carried diagnoses of focal (25%), multifocal (2%), generalized (4%), and unclassified epilepsy (6%), and early-onset epileptic encephalopathy (25%). Most patients had drug-resistant epilepsy. We detail EEG, neuroimaging, developmental, and cognitive features, treatment responsiveness, and physical examination. In silico evaluation revealed 7 different highly conserved motifs, with the most common pathogenic mutation located in the first. Neuronal outgrowth assays showed that some TBC1D24 mutations, associated with the most severe TBC1D24-associated disorders, are not necessarily the most disruptive to this gene function. CONCLUSIONS: TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness (not studied here), benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct correlation with mutation type or location yet, but patterns are emerging. Given the phenotypic breadth observed, TBC1D24 mutation screening is indicated in a wide variety of epilepsies. A TBC1D24 consortium was formed to develop further research on this gene and its associated phenotypes.


Asunto(s)
Proteínas Portadoras/genética , Epilepsia/genética , Epilepsia/fisiopatología , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Proteínas Portadoras/metabolismo , Aumento de la Célula , Células Cultivadas , Niño , Preescolar , Estudios de Cohortes , Electroencefalografía , Epilepsia/diagnóstico por imagen , Epilepsia/psicología , Femenino , Proteínas Activadoras de GTPasa , Estudios de Asociación Genética , Humanos , Lactante , Masculino , Proteínas de la Membrana , Ratones , Mutación , Proteínas del Tejido Nervioso , Neuritas/fisiología , Examen Físico , Adulto Joven
12.
J Pediatr Oncol ; 1: 32-40, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24749125

RESUMEN

BACKGROUND: Pediatric gliomas, the most common solid childhood neoplasm, manifest unique molecular signatures that distinguish them from adult gliomas. Unfortunately, most studies have focused on adult gliomas and extrapolate the findings to treat pediatric gliomas. In this study, we assessed the efficacy of Targetin, a folate conjugated analogue of Noscapine, on the treatment of pediatric low and high grade gliomas. METHOD: An assortment of standard cancer assays were used with different drug doses and experimental durations. RESULTS: We found that pediatric glioma cells are more susceptible to lower doses of Targetin than parental Noscapine. Targetin functions by disrupting the microtubule network, and can likewise perturb DNA synthesis, delay the cellular transition within the S and G2M cell cycle phases, diminish anchorage independent growth and the migratory/invasiveness of pediatric glioma cells. Moreover, Targetin impairs the expression of several regulators of cancer progression belonging to prominent signalling pathways in pediatric gliomas; including Platelet Derived Growth Factor alpha and some members of the Mitogen Activated Protein Kinase cascade. CONCLUSION: Targetin has an excellent anti-neoplastic profile and functions to modulate the expression of several genes belonging to key cancer progression pathways in pediatric gliomas. Collectively, findings from this study highlight the usefulness of Targetin for the treatment of pediatric high and low grade gliomas.

13.
Cancer Lett ; 335(1): 109-18, 2013 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-23402815

RESUMEN

Low grade gliomas are a heterogeneous group of tumours representing the most common form of neoplasms in the central nervous system among children. Although gross total resection remains the principal treatment, it is often impractical especially for the resection of tumours within eloquent regions of the brain. Instead Radiotherapy is utilised in such cases, but because of its associated toxicities, it is refrained from use among younger children. These limitations coupled with hypersensitivity and toxicities associated with some commonly used chemotherapeutic agents, have ignited the need to search for safer and more effective treatments for paediatric low grade gliomas. In this study, we investigated the EM011 drug on the growth of two pilocytic and one diffuse paediatric astrocytoma cell lines, using an assortment of cancer assays. We discovered that treatments of low grade gliomas with EM011 abrogated cell viability by inducing a decrease in cell proliferation and an arrest in the S and G2M cell cycle phases, followed by a converse increase in apoptosis in a dose and time dependent manner. The cell migratory and invasion indices, as well as anchorage independent growth in soft agarose, were significantly attenuated. These findings were mechanistically associated with a transient release of AIF, a disruption of microtubule architecture, and a decline in the expression of key genes which drive cancer progression including EGFR, mTORC1, JUN and multiple MMPs. In fact, the activity of MMP2 was also perturbed by EM011. These findings, in conjunction with the insignificant adverse side effects established from other studies, make EM011 an appealing chemotherapeutic agent for the treatment of paediatric low grade gliomas.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Dioxoles/farmacología , Glioma/tratamiento farmacológico , Isoquinolinas/farmacología , Moduladores de Tubulina/farmacología , Apoptosis/efectos de los fármacos , Factor Inductor de la Apoptosis/metabolismo , Neoplasias Encefálicas/patología , Adhesión Celular , Línea Celular Tumoral/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Niño , Gelatinasas/metabolismo , Expresión Génica/efectos de los fármacos , Glioma/patología , Humanos , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Clasificación del Tumor , Puntos de Control de la Fase S del Ciclo Celular/efectos de los fármacos , Transcriptoma
14.
J Pediatr Oncol ; 1: 41-47, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24749126

RESUMEN

BACKGROUND: Intervention aimed at disrupting or inhibiting newly formed vascular network is highly desired to attenuate the progression of angiogenesis-dependent diseases. In cancer, this is tightly associated with the generation of VEGF by hypoxia inducible factor-1α following its activation by hypoxia. In light of the multiple cellular roles played by microtubules and their involvement in the processing of the hypoxia inducible factor-1α transcript, modulation of microtubule dynamics is emerging as a logical approach to suppress tumor reliance on angiogenesis. Targetin is a novel noscapinoid that interferes with microtubule dynamicity and inhibits the growth of cell lines from many types of cancers. METHODS AND RESULTS: Utilizing in-vitro and ex-vivo angiogenic models, we discovered the vascular disrupting and anti-angiogenic properties of Targetin. Targetin disrupted pre-assembled capillary-like networks of human endothelial cells by severing cell-cell junctions, inhibiting endothelial cell proliferation and metabolic activity in the presence and absence of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Furthermore, we show that Targetin significantly inhibits the formation of neovasculature network sprouting from rat aortic explants stimulated with proangiogenic stimuli, namely VEGF or bFGF. CONCLUSION: We conclude that Targetin is a potential clinically promising anti-angiogenic agent for the treatment of many diseases including cancers.

SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA