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1.
Nat Chem Biol ; 8(2): 185-96, 2011 Dec 25.
Artículo en Inglés | MEDLINE | ID: mdl-22198733

RESUMEN

Protein homeostasis (proteostasis) is essential for cellular and organismal health. Stress, aging and the chronic expression of misfolded proteins, however, challenge the proteostasis machinery and the vitality of the cell. Enhanced expression of molecular chaperones, regulated by heat shock transcription factor-1 (HSF-1), has been shown to restore proteostasis in a variety of conformational disease models, suggesting this mechanism as a promising therapeutic approach. We describe the results of a screen comprised of ∼900,000 small molecules that identified new classes of small-molecule proteostasis regulators that induce HSF-1-dependent chaperone expression and restore protein folding in multiple conformational disease models. These beneficial effects to proteome stability are mediated by HSF-1, FOXO, Nrf-2 and the chaperone machinery through mechanisms that are distinct from current known small-molecule activators of the heat shock response. We suggest that modulation of the proteostasis network by proteostasis regulators may be a promising therapeutic approach for the treatment of a variety of protein conformational diseases.


Asunto(s)
Evaluación Preclínica de Medicamentos , Chaperonas Moleculares/efectos de los fármacos , Proteínas/efectos de los fármacos , Deficiencias en la Proteostasis/tratamiento farmacológico , Factores de Transcripción/efectos de los fármacos , Animales , Caenorhabditis elegans , Línea Celular , Proteínas de Unión al ADN/efectos de los fármacos , Factores de Transcripción Forkhead/efectos de los fármacos , Factores de Transcripción del Choque Térmico , Homeostasis/efectos de los fármacos , Humanos , Factor 2 Relacionado con NF-E2/efectos de los fármacos , Conformación Proteica/efectos de los fármacos , Proteínas/química , Proteínas/fisiología , Ratas
2.
PLoS One ; 5(4): e9934, 2010 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-20376192

RESUMEN

BACKGROUND: Hsp90 is an essential molecular chaperone that is also a novel anti-cancer drug target. There is growing interest in developing new drugs that modulate Hsp90 activity. METHODOLOGY/PRINCIPAL FINDINGS: Using a virtual screening approach, 4-hydroxytamoxifen, the active metabolite of the anti-estrogen drug tamoxifen, was identified as a putative Hsp90 ligand. Surprisingly, while all drugs targeting Hsp90 inhibit the chaperone ATPase activity, it was found experimentally that 4-hydroxytamoxifen and tamoxifen enhance rather than inhibit Hsp90 ATPase. CONCLUSIONS/SIGNIFICANCE: Hence, tamoxifen and its metabolite are the first members of a new pharmacological class of Hsp90 activators.


Asunto(s)
Adenosina Trifosfatasas/efectos de los fármacos , Proteínas HSP90 de Choque Térmico/agonistas , Tamoxifeno/farmacología , Adenosina Trifosfatasas/metabolismo , Antineoplásicos Hormonales , Simulación por Computador , Evaluación Preclínica de Medicamentos , Humanos , Chaperonas Moleculares/efectos de los fármacos , Tamoxifeno/análogos & derivados
3.
Exp Gerontol ; 43(5): 452-61, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18304769

RESUMEN

Chaperones and zinc are indispensable for proper immune function. All the zinc status, the immune function and the stress response decline during aging. Here we studied the effect of nutritional zinc and zinc homeostasis on the stress response in healthy old subjects recruited during the ZincAge European Union project that either underwent or not a 48-day zinc supplementation. Inducible Hsp70 levels were determined at basal conditions as well as after heat shock in the CD3+ and CD3- subset of lymphocytes by a two-color FACS analysis. Short term zinc supplementation resulted in a marked increase in both basal as well as stress-induced Hsp70 levels in lymphocytes from healthy elderly donors with a higher impact on CD3+ cells. Heat inducibility showed a strong correlation with basal Hsp70 level, and both basal as well as stress-induced Hsp70 highly correlated with intracellular zinc availability. In conclusion, short term oral supplementation with zinc safely and efficiently induces the stress response in lymphocytes of old donors. The stress response may be a candidate pathway connecting zinc deficiency with aging and immunosenescence. Thus, proper dietary zinc intake may emerge as a chaperone inducer and an anti-aging mechanism in the immune system.


Asunto(s)
Proteínas HSP70 de Choque Térmico/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Estrés Fisiológico/inmunología , Oligoelementos/farmacología , Zinc/farmacología , Anciano , Anciano de 80 o más Años , Proteínas de Unión al ADN/metabolismo , Suplementos Dietéticos , Factores de Transcripción del Choque Térmico , Humanos , Inmunidad Celular/efectos de los fármacos , Persona de Mediana Edad , Chaperonas Moleculares/efectos de los fármacos , Oligoelementos/administración & dosificación , Factores de Transcripción/metabolismo , Zinc/administración & dosificación
4.
Br J Pharmacol ; 143(2): 318-30, 2004 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-15339863

RESUMEN

The human (h) and mouse (m) prostacyclin receptors (IPs) undergo isoprenylation through attachment of a C-15 farnesyl moiety within their conserved carboxyl terminal -CSLC sequences. Herein, the effects of a novel farnesyl transferase inhibitor R115777 on signalling by the hIP and mIP, overexpressed in human embryonic kidney 293 cells, and by the hIP endogenously expressed in human erythroleukaemia cells were investigated. R115777 significantly impaired IP-mediated cyclic AMP generation (IC(50) 0.37-0.60 nm) and intracellular calcium ([Ca(2+)](i)) mobilization (IC(50) 37-65 nm), but had no effect on signalling by the control nonisoprenylated beta(2) adrenergic receptor or the alpha or beta isoforms of the human thromboxane A(2) receptor (TP). Additionally, R115777 significantly reduced IP-mediated cross-desensitization of signalling by the TP alpha, but not by the TP beta, isoform of the human TP and impaired the farnesylation-dependent processing of the chaperone HDJ-2 protein (IC(50) 4.5 nm). Furthermore, R115777 fully impaired isoprenylation of both the Ha-Ras(WT) and Ha-Ras(CSLC) in vitro and in whole cells confirming that, unlike N-Ras and Ki-Ras, the -CSLC motif associated with the IP cannot support alternative geranylgeranylation in the presence of R115777 and does not act as a substrate for geranylgeranyl transferase 1 in vitro or in whole cells. In conclusion, these data confirm that R115777 potently impairs IP isoprenylation and signalling, and suggest that clinically it may not only target Ras proteins but may also disrupt IP isoprenylation, events which could impact on physiologic processes in which prostacyclin and its receptor are implicated.


Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Transferasas Alquil y Aril/farmacología , Inhibidores Enzimáticos/farmacología , Quinolonas/farmacología , Transferasas/antagonistas & inhibidores , Transferasas/farmacología , Animales , Calcio/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Humanos , Iloprost/farmacología , Irlanda , Ratones , Chaperonas Moleculares/efectos de los fármacos , Chaperonas Moleculares/metabolismo , Organofosfonatos , Prenilación de Proteína/efectos de los fármacos , Quinolonas/química , Receptor Cross-Talk/efectos de los fármacos , Receptor Cross-Talk/fisiología , Receptores de Prostaglandina/clasificación , Receptores de Prostaglandina/efectos de los fármacos , Receptores de Prostaglandina/genética , Factores de Tiempo , Transfección/métodos , Transferasas/metabolismo , Tritio
5.
Expert Opin Ther Targets ; 7(2): 201-13, 2003 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-12667098

RESUMEN

Huntington's disease (HD) is one of a number of familial polyglutamine (polyQ) repeat diseases. These neurodegenerative disorders are caused by expression of otherwise unrelated proteins that contain an expansion of a polyQ tract, rendering them toxic to specific subsets of vulnerable neurons. These expanded repeats have an inherent propensity to aggregate; insoluble neuronal nuclear and cytoplasmic polyQ aggregates or inclusions are hallmarks of the disorders [1,2]. In HD, inclusions in diseased brains often precede onset of symptoms, and have been proposed to be involved in pathogenicity [3-5]. Various strategies to block the process of aggregation have been developed in an effort to create drugs that decrease neurotoxicity. A discussion of the effect of antibodies, caspase inhibitors, chemical inhibitors, heat-shock proteins, suppressor peptides and transglutaminase inhibitors upon aggregation and disease is presented.


Asunto(s)
Expansión de las Repeticiones de ADN , Diseño de Fármacos , Enfermedad de Huntington/tratamiento farmacológico , Proteínas del Tejido Nervioso/efectos de los fármacos , Nootrópicos/farmacología , Proteínas Nucleares/efectos de los fármacos , Péptidos/genética , Transporte Activo de Núcleo Celular/efectos de los fármacos , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Proteínas de Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/efectos de los fármacos , Proteínas de Caenorhabditis elegans/fisiología , Inhibidores de Cisteína Proteinasa/farmacología , Inhibidores de Cisteína Proteinasa/uso terapéutico , Proteínas de Drosophila/química , Proteínas de Drosophila/efectos de los fármacos , Proteínas de Drosophila/fisiología , Evaluación Preclínica de Medicamentos , Humanos , Proteína Huntingtina , Enfermedad de Huntington/genética , Cuerpos de Inclusión Intranucleares/química , Cuerpos de Inclusión Intranucleares/efectos de los fármacos , Ratones , Ratones Transgénicos , Mitocondrias/efectos de los fármacos , Mitocondrias/fisiología , Chaperonas Moleculares/efectos de los fármacos , Chaperonas Moleculares/fisiología , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Nootrópicos/uso terapéutico , Proteínas Nucleares/química , Proteínas Nucleares/genética , Conformación Proteica , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Interferencia de ARN , Secuencias Repetitivas de Aminoácido , Transcripción Genética/efectos de los fármacos
6.
Urology ; 58(2 Suppl 1): 39-49, 2001 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-11502446

RESUMEN

BACKGROUND: Androgen resistance develops, in part, from upregulation of antiapoptotic genes after androgen withdrawal. Identification and targeting of genes mediating androgen-independent (AI) progression may lead to development of novel therapies that delay hormone-refractory prostate cancer. Clusterin is a cell survival gene, that increases after androgen ablation. Here, we review clusterin's functional role in apoptosis and the ability of antisense oligonucleotides (ASOs) against clusterin to enhance apoptosis in prostate cancer xenograft models. RESULTS: Immunostaining of radical prostatectomy specimens confirm that clusterin is highly expressed in 80% prostate cancer cells after neoadjuvant hormone therapy, but is low or absent (<20%) in untreated specimens. Clusterin levels increase >10 fold in regressing Shionogi tumors after castration. Pretreatment of mice bearing androgen-dependent Shionogi tumors with calcium antagonists inhibited castration-induced apoptosis, tumor regression, and clusterin gene upregulation, illustrating that clusterin is an apoptosis-associated gene and not an androgen-repressed gene. Clusterin ASOs reduced clusterin levels in a dose-dependent and sequence-specific manner. Adjuvant treatment with murine clusterin ASOs after castration of mice bearing Shionogi tumors decreased clusterin levels by 70% and resulted in earlier onset and more rapid apoptotic tumor regression, with significant delay in recurrence of AI tumors. Species-specific clusterin ASOs also increased the cytotoxic effects of paclitaxel, reducing the 50% inhibitory concentration (IC(50)) of PC-3 and Shionogi cells by 75% to 90%. Although clusterin ASOs had no effect on the growth of established AI Shionogi or PC-3 tumors, clusterin ASOs synergistically enhanced paclitaxel-induced tumor regression in both Shionogi and PC-3 models. CONCLUSIONS: Collectively, these data identify clusterin as an antiapoptosis protein, upregulated in an adaptive cell-survival manner by androgen ablation and chemotherapy, which confers resistance to various cell-death triggers. Inhibition of clusterin upregulation using clusterin ASOs can enhance cell death after treatment with androgen ablation and chemotherapy.


Asunto(s)
Apoptosis/genética , Glicoproteínas/efectos de los fármacos , Glicoproteínas/genética , Chaperonas Moleculares/efectos de los fármacos , Chaperonas Moleculares/genética , Oligonucleótidos Antisentido/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Antagonistas de Andrógenos/farmacología , Antagonistas de Andrógenos/uso terapéutico , Animales , Antineoplásicos Hormonales/farmacología , Antineoplásicos Hormonales/uso terapéutico , Apoptosis/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Bloqueadores de los Canales de Calcio/uso terapéutico , Muerte Celular/efectos de los fármacos , Clusterina , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Humanos , Masculino , Ratones , Terapia Neoadyuvante/métodos , Oligonucleótidos Antisentido/farmacología , Orquiectomía , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Neoplasias de la Próstata/genética , Regulación hacia Arriba/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
7.
Br J Pharmacol ; 131(8): 1577-83, 2000 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11139434

RESUMEN

To better understand the anticancer activity of Levamisole (LMS), which serves as an adjuvant in colon cancer therapy in combination with 5-Fluorouracil, this study analyses LMS' ability to induce apoptosis and growth arrest in cultured human micro- and macrovascular endothelial cells (ECs) and fibroblasts. Cells exposed (24 h) to Levamisole (range: 0.5 - 2 mmol l(-1)) alone or in combination with antioxidants (10 mmol l(-1) glutathione or 5 mmol l(-1) N-Acetylcysteine or 0.1 mmol l(-1) Tocopherol) were evaluated for apoptosis ((3)H-thymidine assays, in situ staining), mRNA/protein expression (Northern/Western blot), and proliferation ((3)H-thymidine incorporation). Levamisole dose-dependently increased apoptosis in ECs to 230% (HUVECs-human umbilical vein ECs), 525% (adult human venous ECs) and 600% (human uterine microvascular ECs) but not in fibroblasts compared to control cells (set as 100%). Levamisole increased in ECs integrin-dependent matrix adhesion, inhibited proliferation (-70%), reduced expression of survival factors such as clusterin (-30%), endothelin-1 (-43%), bcl-2 (-34%), endothelial NO-synthase (-32%) and pRb (Retinoblastoma protein: -89%), and increased that of growth arrest/death signals such as p21 (+73%) and bak (+50%). LMS (2 mmol l(-1))-induced apoptosis was inhibited by glutathione (-50%) and N-Acetylcysteine (-36%), which also counteracted reduction by Levamisole of pRb expression, suggesting reactive oxygen species and pRb play a role in these processes. The ability of LMS to selectively induce apoptosis and growth arrest in endothelial cells potentially hints at vascular targeting to contribute to Levamisole's anticancer activity.


Asunto(s)
Apoptosis/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Levamisol/farmacología , Acetilcisteína/farmacología , Antioxidantes/farmacología , Capilares/citología , Capilares/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Recuento de Células , División Celular/efectos de los fármacos , Células Cultivadas , Clusterina , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Ciclinas/efectos de los fármacos , Ciclinas/genética , Ciclinas/metabolismo , Relación Dosis-Respuesta a Droga , Endotelina-1/efectos de los fármacos , Endotelina-1/genética , Endotelina-1/metabolismo , Endotelio Vascular/citología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Glutatión/farmacología , Glicoproteínas/efectos de los fármacos , Glicoproteínas/genética , Glicoproteínas/metabolismo , Humanos , Proteínas de la Membrana/efectos de los fármacos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Chaperonas Moleculares/efectos de los fármacos , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , ARN Mensajero/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteína de Retinoblastoma/efectos de los fármacos , Proteína de Retinoblastoma/genética , Proteína de Retinoblastoma/metabolismo , Vena Safena/citología , Vena Safena/efectos de los fármacos , Timidina/metabolismo , Tritio , Proteína p53 Supresora de Tumor/efectos de los fármacos , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Venas Umbilicales/citología , Venas Umbilicales/efectos de los fármacos , Útero/irrigación sanguínea
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