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[PMID]:29231931
[Au] Autor:Imani Nejad M; Yang D; Shen B; Gates KS
[Ad] Endereço:Department of Chemistry, University of Missouri, 125 Chemistry Bldg, Columbia, MO 65211, USA. gatesk@missouri.edu.
[Ti] Título:Oxidative activation of leinamycin E1 triggers alkylation of guanine residues in double-stranded DNA.
[So] Source:Chem Commun (Camb);54(3):256-259, 2018 Jan 02.
[Is] ISSN:1364-548X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:It may be useful to develop prodrugs that are selectively activated by oxidative stress in cancer cells to release cell-killing reactive intermediates. However, relatively few chemical strategies exist for the activation of prodrugs under conditions of oxidative stress. Here we provide evidence for a novel process in which oxidation of a thiol residue in the natural product leinamycin E1 by H O and other byproducts of cellular oxidative stress initiates generation of an episulfonium ion that selectively alkylates guanine residues in duplex DNA.
[Mh] Termos MeSH primário: Antineoplásicos Alquilantes/química
DNA/química
Guanina/química
Lactamas Macrocíclicas/química
Pró-Fármacos/química
[Mh] Termos MeSH secundário: Alquilação
Antineoplásicos Alquilantes/síntese química
Dano ao DNA
Compostos Férricos/química
Peróxido de Hidrogênio/química
Lactamas Macrocíclicas/síntese química
Oxirredução
Pró-Fármacos/síntese química
Xantina/química
Xantina Oxidase/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents, Alkylating); 0 (Ferric Compounds); 0 (Lactams, Macrocyclic); 0 (Prodrugs); 0 (leinamycin E1); 1AVZ07U9S7 (Xanthine); 5Z93L87A1R (Guanine); 9007-49-2 (DNA); BBX060AN9V (Hydrogen Peroxide); EC 1.17.3.2 (Xanthine Oxidase); LUX2X1H1IC (ammonium ferric sulfate)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171213
[St] Status:MEDLINE
[do] DOI:10.1039/c7cc08482j


  2 / 2983 MEDLINE  
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[PMID]:29179175
[Au] Autor:Tu RH; Li QJ; Huang Z; He Y; Meng JJ; Zheng HL; Zeng ZY; Zhong GQ
[Ad] Endereço:Department of Geriatric Cardiology, Nanning, China.
[Ti] Título:Novel Functional Role of Heat Shock Protein 90 in Mitochondrial Connexin 43-Mediated Hypoxic Postconditioning.
[So] Source:Cell Physiol Biochem;44(3):982-997, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: Previous studies have shown that heat shock protein 90 (HSP90)-mediated mitochondrial import of connexin 43 (Cx43) is critical in preconditioning cardioprotection. The present study was designed to test whether postconditioning has the same effect as preconditioning in promoting Cx43 translocation to mitochondria and whether mitochondrial HSP90 modulates this effect. METHODS: Cellular models of hypoxic postconditioning (HPC) from rat heart-derived H9c2 cells and neonatal rat cardiomyocytes were employed. The effects of HPC on cardiomyocytes apoptosis were examined by flow cytometry and Hoechst 33342 fluorescent staining. Reactive oxidative species (ROS) production was assessed with the peroxide-sensitive fluorescent probe 2',7'-dichlorofluorescin in diacetate (DCFH-DA). The anti- and pro-apoptotic markers Bcl-2 and Bax, HSP90 and Cx43 protein levels were studied by Western blot analysis in total cell homogenate and sarcolemmal and mitochondrial fractions. The effects on HPC of the HSP90 inhibitor geldanamycin (GA), ROS scavengers superoxide dismutase (SOD) and catalase (CAT), and small interfering RNA (siRNA) targeting Cx43 and HSP90 were also investigated. RESULTS: HPC significantly reduced hypoxia/reoxygenation (H/R)-induced cardiomyocyte apoptosis. These beneficial effects were accompanied by an increase in Bcl-2 levels and a decrease in Bax levels in both sarcolemmal and mitochondrial fractions. HPC with siRNA targeting Cx43 or the ROS scavengers SOD plus CAT significantly prevented ROS generation and HPC cardioprotection, but HPC with either SOD or CAT did not. These data strongly supported the involvement of Cx43 in HPC cardioprotection, likely via modulation of the ROS balance which plays a central role in HPC protection. Furthermore, HPC increased total and mitochondrial levels of HSP90 and the mitochondria-to-sarcolemma ratio of Cx43; blocking the function of HSP90 with the HSP90 inhibitor geldanamycin (GA) or siRNA targeting HSP90 prevented the protection of HPC and the HPC-induced association of Cx43, indicating that mitochondrial HSP90 was important for mitochondrial translocation of Cx43 during HPC. CONCLUSION: Mitochondrial HSP90 played a central role in HPC cardioprotection, and its activity was linked to the mitochondrial targeting of Cx43, the activation of which triggered ROS signaling and the subsequent reduction of redox stress. Consequently, its target gene, Bcl-2, was upregulated, and proapoptotic Bax was inhibited in the sarcolemma and mitochondria, ultimately attenuating H/R-induced cardiomyocyte apoptosis. These data reveal a novel mechanism of HPC protection.
[Mh] Termos MeSH primário: Conexina 43/metabolismo
Proteínas de Choque Térmico HSP90/metabolismo
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Benzoquinonas/farmacologia
Catalase/farmacologia
Hipóxia Celular
Linhagem Celular
Conexina 43/antagonistas & inibidores
Conexina 43/genética
Proteínas de Choque Térmico HSP90/antagonistas & inibidores
Proteínas de Choque Térmico HSP90/genética
Lactamas Macrocíclicas/farmacologia
Microscopia de Fluorescência
Mitocôndrias/metabolismo
Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
Interferência de RNA
RNA Interferente Pequeno/metabolismo
Ratos
Ratos Sprague-Dawley
Espécies Reativas de Oxigênio/química
Espécies Reativas de Oxigênio/metabolismo
Sarcolema/metabolismo
Superóxido Dismutase/farmacologia
Proteína X Associada a bcl-2/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzoquinones); 0 (Connexin 43); 0 (HSP90 Heat-Shock Proteins); 0 (Lactams, Macrocyclic); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (RNA, Small Interfering); 0 (Reactive Oxygen Species); 0 (bcl-2-Associated X Protein); EC 1.11.1.6 (Catalase); EC 1.15.1.1 (Superoxide Dismutase); Z3K3VJ16KU (geldanamycin)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180118
[Lr] Data última revisão:
180118
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1159/000485399


  3 / 2983 MEDLINE  
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[PMID]:29227608
[Au] Autor:Golovenko NY; Larionov VB; Karpova OV
[Ti] Título:Physical-chemical properties and the reactivity of pyridoxine and pyrrolidone carboxylate and their protolytic forms.
[So] Source:Ukr Biochem J;88(2):73-81, 2016 Mar-Apr.
[Is] ISSN:2409-4943
[Cp] País de publicação:Ukraine
[La] Idioma:eng
[Ab] Resumo:Preparation Methadoxine is equimolar salt, which cationic component (pyridoxine) is 3-oxypyridine derivative, possessing B6-vitamine like activity, while anionic component is the cyclic lactame of glutamic acid. Since biopharmaceutical and pharmacological properties of this drug depend on biochemical transformation its components, of the aim of this work was to determine the structure of possible ionized pyridoxine and pyrrolidone carboxylate forms and their reaction ability in biochemical processes. Physical-chemical properties of compounds (pKa, logP, logD, proton donor/acceptor quantity, solubility (g/l)) were calculated with ACD/pKaDB program or obtained from Pub-Med physical/chemical properties database. UV spectra of compounds were obtained after dissolution in different pH solutions (1.0, 4.5 and 6.8). It was found that at different pH values one can observe changes of the absorption spectra due to the presence of prevailing amount of the protonated form. An analysis of both pKa, logP and logD indicators and reactive functional groups of Methadoxine components has revealed that they can be protonated in different regions of gastro-intestinal tract, that influences their solubility in hydrophilic and lypophilic media. Pharmacological properties of pyridoxine and pyrrolidone carboxylate themselves are performed after their preliminary biotransformation to active metabolites. Only ionic interaction between Methadoxine components in the substance composition can appear, that provides its pharmaceutical stability and ensures its activity only in the organism conditions.
[Mh] Termos MeSH primário: Ácido Glutâmico/química
Lactamas Macrocíclicas/química
Prótons
Piridoxina/química
Ácido Pirrolidonocarboxílico/química
[Mh] Termos MeSH secundário: Estabilidade de Medicamentos
Concentração de Íons de Hidrogênio
Interações Hidrofóbicas e Hidrofílicas
Solubilidade
Soluções
Espectrofotometria Ultravioleta
Água/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Lactams, Macrocyclic); 0 (Protons); 0 (Solutions); 059QF0KO0R (Water); 3KX376GY7L (Glutamic Acid); KV2JZ1BI6Z (Pyridoxine); SZB83O1W42 (Pyrrolidonecarboxylic Acid)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171212
[St] Status:MEDLINE
[do] DOI:10.15407/ubj88.02.073


  4 / 2983 MEDLINE  
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[PMID]:28450396
[Au] Autor:Lei W; Mullen N; McCarthy S; Brann C; Richard P; Cormier J; Edwards K; Bilsky EJ; Streicher JM
[Ad] Endereço:From the Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona 85724.
[Ti] Título:Heat-shock protein 90 (Hsp90) promotes opioid-induced anti-nociception by an ERK mitogen-activated protein kinase (MAPK) mechanism in mouse brain.
[So] Source:J Biol Chem;292(25):10414-10428, 2017 06 23.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Recent advances in developing opioid treatments for pain with reduced side effects have focused on the signaling cascades of the µ-opioid receptor (MOR). However, few such signaling targets have been identified for exploitation. To address this need, we explored the role of heat-shock protein 90 (Hsp90) in opioid-induced MOR signaling and pain, which has only been studied in four previous articles. First, in four cell models of MOR signaling, we found that Hsp90 inhibition for 24 h with the inhibitor 17- -allylamino-17-demethoxygeldanamycin (17-AAG) had different effects on protein expression and opioid signaling in each line, suggesting that cell models may not be reliable for predicting pharmacology with this protein. We thus developed an model using CD-1 mice with an intracerebroventricular injection of 17-AAG for 24 h. We found that Hsp90 inhibition strongly blocked morphine-induced anti-nociception in models of post-surgical and HIV neuropathic pain but only slightly blocked anti-nociception in a naive tail-flick model, while enhancing morphine-induced precipitated withdrawal. Seeking a mechanism for these changes, we found that Hsp90 inhibition blocks ERK MAPK activation in the periaqueductal gray and caudal brain stem. We tested these signaling changes by inhibiting ERK in the above-mentioned pain models and found that ERK inhibition could account for all of the changes in anti-nociception induced by Hsp90 inhibition. Taken together, these findings suggest that Hsp90 promotes opioid-induced anti-nociception by an ERK mechanism in mouse brain and that Hsp90 could be a future target for improving the therapeutic index of opioid drugs.
[Mh] Termos MeSH primário: Analgésicos Opioides/farmacologia
Benzoquinonas/farmacologia
Tronco Encefálico/metabolismo
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Proteínas de Choque Térmico HSP90/metabolismo
Lactamas Macrocíclicas/farmacologia
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
Nociceptividade/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Tronco Encefálico/patologia
Células CHO
Cricetinae
Cricetulus
Células HEK293
Seres Humanos
Masculino
Camundongos
Neuralgia/tratamento farmacológico
Neuralgia/metabolismo
Neuralgia/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Analgesics, Opioid); 0 (Benzoquinones); 0 (HSP90 Heat-Shock Proteins); 0 (Lactams, Macrocyclic); 4GY0AVT3L4 (tanespimycin); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171229
[Lr] Data última revisão:
171229
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.769489


  5 / 2983 MEDLINE  
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[PMID]:29061812
[Au] Autor:Nam S; Kim H; Hong D; Park JB; Kim SJ
[Ad] Endereço:Department of Health Sciences & Technology, Graduate School, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, Republic of Korea.
[Ti] Título:Tumor Suppression Efficacy of Heat Shock Protein 90 Inhibitor 17AAG in a Liposarcoma Mouse Model.
[So] Source:Anticancer Res;37(11):6291-6302, 2017 11.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIM: Heat shock protein 90 (HSP90) inhibitors have recently been tested as anticancer drugs in a variety of carcinomas. Yet, there exist only few reports about HSP90 inhibitor and its thepeutic effect on liposarcoma. The therapeutic effects of HSP90 inhibitors have been mainly observed in oncogenic and tumor angiogenic signaling cascades by observing tumor growth. MATERIALS AND METHODS: We used the the LPS 246 liposarcoma cell line and GS-076 PDC (patient-derived cell lines). On these, we performed cell viability assays and migration assays under treatment with the HSP90 inhibitor, 17AAG. For analyzing angiogenesis factor, we used quantitative polymerase chain reaction (qPCR) after treating cells with the 17AAG inhibitor. Regarding in vivo assay, we made the tumor model in immune-deficient mouse and compared the tumor size of drug-treated group at each time point with controls. For sequestering analysis of angiogenesis factor in vivo, we performed immuno-fluorescence (IF) staining on tumor tissue. RESULTS: Through cell viability, migration assay and qPCR about angiogenesis factor, we demonstrated the anti-oncogenic and anti-angiogenic effects of an HSP90 inhibitor on a liposarcoma cell line and a patient-derived primary cell model (PDC). Also, the HSP90 inhibitor 17AAG effectively inhibited the activity of protein kinase B (AKT) and blocked extracellular signal-regulated kinase (ERK) activity. Hence, 17AAG effectively disrupted the oncogenic signaling cascade and substantially inhibited tumor growth in vitro. In an LPS 863 cell xenograft mouse model treated with 17AAG, we observed that tumor size was decreasing, as well as down-regulation of the expression levels of vascular endothelial growth factor receptor 2 (VEGFR2), CD31 and signal transducer and activator of transcription-3 (STAT3). CONCLUSION: 17AAG reduced the activity of AKT, ERK, VEGF and STAT3 in oncogenic and angiogenic pathways in liposarcoma PDC models derived from patients' tissues and cancer cell lines.
[Mh] Termos MeSH primário: Inibidores da Angiogênese/administração & dosagem
Antineoplásicos/administração & dosagem
Benzoquinonas/administração & dosagem
Proteínas de Choque Térmico HSP90/antagonistas & inibidores
Lactamas Macrocíclicas/administração & dosagem
Lipossarcoma/tratamento farmacológico
[Mh] Termos MeSH secundário: Inibidores da Angiogênese/farmacologia
Animais
Antineoplásicos/farmacologia
Benzoquinonas/farmacologia
Linhagem Celular Tumoral
Movimento Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Lactamas Macrocíclicas/farmacologia
Lipossarcoma/genética
Lipossarcoma/metabolismo
Camundongos
Fator de Transcrição STAT3/genética
Fator de Transcrição STAT3/metabolismo
Transdução de Sinais/efeitos dos fármacos
Carga Tumoral/efeitos dos fármacos
Fator A de Crescimento do Endotélio Vascular/genética
Fator A de Crescimento do Endotélio Vascular/metabolismo
Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiogenesis Inhibitors); 0 (Antineoplastic Agents); 0 (Benzoquinones); 0 (HSP90 Heat-Shock Proteins); 0 (Lactams, Macrocyclic); 0 (STAT3 Transcription Factor); 0 (STAT3 protein, human); 0 (VEGFA protein, human); 0 (Vascular Endothelial Growth Factor A); 4GY0AVT3L4 (tanespimycin); EC 2.7.10.1 (KDR protein, human); EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171025
[St] Status:MEDLINE


  6 / 2983 MEDLINE  
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[PMID]:29034805
[Au] Autor:Vural K; Kosova F; Kurt FÖ; Tuglu I
[Ad] Endereço:1 Department of Medical Pharmacology, Faculty of Medicine, Celal Bayar University, Manisa, Turkey.
[Ti] Título:In vitro investigation of the effect of matrix molecules on the behavior of colon cancer cells under the effect of geldanamycin derivative.
[So] Source:Tumour Biol;39(10):1010428317720569, 2017 Oct.
[Is] ISSN:1423-0380
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The chaperone-binding drug, 17-allylamino-17-demethoxygeldanamycin, has recently come into clinical use. It is a derivative of geldanamycin, an ansamycin benzoquinone antibiotic with anti-carcinogenic effect. Understanding the effect of this drug on the cancer cells and their niche is important for treatment. We applied 17-allylamino-17-demethoxygeldanamycin to colon cancer cell line (Colo 205) on matrix molecules to investigate the relationship of apoptosis with terminal deoxynucleotidyl transferase dUTP nick end labeling immunocytochemistry and related gene expression. We used laminin and collagen I for matrix molecules and vascular endothelial growth factor for angiogenic structure. We also examined apoptosis-related signaling pathway including mitochondrial proteins, cytochrome c, Bcl-2, caspase-9, Apaf-1 expression using real-time polymerase chain reaction. There was clear effect of 17-allylamino-17-demethoxygeldanamycin that killed more cells on tissue culture plastic compared to matrix molecules. The IC value was 0.58 µg/mL for tissue culture plastic compared with 0.64 µg/mL for laminin and 0.75 µg/mL for collagen I. The analyses showed that more cells on matrix molecules underwent apoptosis compared to that on tissue culture plastic. Apoptosis-related gene expression was similar in which Bcl-2 expression decreased and proapoptotic gene expression of the cells on matrix molecules increased compared to that on tissue culture plastic. However, the application of 17-allylamino-17-demethoxygeldanamycin was more effective for the cells on collagen I compared to the cells on laminin. There was also a decrease in angiogenesis as shown by the vascular endothelial growth factor staining. This was more pronounced by coating of the tissue culture plastic with matrix molecules. Our results supported the anti-cancer effect of 17-allylamino-17-demethoxygeldanamycin, and this effect depended on matrix molecules. This effect occurs through apoptosis, and related genes were also altered. All these genes may serve for novel target under the effect of matrix substrate. However, correct interpretation of the results requires further studies.
[Mh] Termos MeSH primário: Anticarcinógenos/farmacologia
Benzoquinonas/farmacologia
Neoplasias do Colo/tratamento farmacológico
Neoplasias do Colo/metabolismo
Lactamas Macrocíclicas/farmacologia
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Fator Apoptótico 1 Ativador de Proteases/metabolismo
Caspase 9/metabolismo
Linhagem Celular Tumoral
Colágeno/metabolismo
Colo/efeitos dos fármacos
Colo/metabolismo
DNA Nucleotidilexotransferase/metabolismo
Seres Humanos
Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
Rifabutina/farmacologia
Transdução de Sinais/efeitos dos fármacos
Fator A de Crescimento do Endotélio Vascular/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticarcinogenic Agents); 0 (Apoptotic Protease-Activating Factor 1); 0 (Benzoquinones); 0 (Lactams, Macrocyclic); 0 (Proto-Oncogene Proteins c-bcl-2); 0 (Vascular Endothelial Growth Factor A); 1W306TDA6S (Rifabutin); 3T006GV98U (quinone); 4GY0AVT3L4 (tanespimycin); 9007-34-5 (Collagen); EC 2.7.7.31 (DNA Nucleotidylexotransferase); EC 3.4.22.- (Caspase 9); Z3K3VJ16KU (geldanamycin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171020
[Lr] Data última revisão:
171020
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171017
[St] Status:MEDLINE
[do] DOI:10.1177/1010428317720569


  7 / 2983 MEDLINE  
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[PMID]:28844885
[Au] Autor:Rajesh Y; Biswas A; Mandal M
[Ad] Endereço:School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur 721302, India.
[Ti] Título:Glioma progression through the prism of heat shock protein mediated extracellular matrix remodeling and epithelial to mesenchymal transition.
[So] Source:Exp Cell Res;359(2):299-311, 2017 Oct 15.
[Is] ISSN:1090-2422
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Glial tumor is one of the intrinsic brain tumors with high migratory and infiltrative potential. This essentially contributes to the overall poor prognosis by circumvention of conventional treatment regimen in glioma. The underlying mechanism in gliomagenesis is bestowed by two processes- Extracellular matrix (ECM) Remodeling and Epithelial to mesenchymal transition (EMT). Heat Shock Family of proteins (HSPs), commonly known as "molecular chaperons" are documented to be upregulated in glioma. A positive correlation also exists between elevated expression of HSPs and invasive capacity of glial tumor. HSPs overexpression leads to mutational changes in glioma, which ultimately drive cells towards EMT, ECM modification, malignancy and invasion. Differential expression of HSPs - a factor providing cytoprotection to glioma cells, also contributes towards its radioresistance /chemoresistance. Various evidences also display upregulation of EMT and ECM markers by various heat shock inducing proteins e.g. HSF-1. The aim of this review is to study in detail the role of HSPs in EMT and ECM leading to radioresistance/chemoresistance of glioma cells. The existing treatment regimen for glioma could be enhanced by targeting HSPs through immunotherapy, miRNA and exosome mediated strategies. This could be envisaged by better understanding of molecular mechanisms underlying glial tumorigenesis in relation to EMT and ECM remodeling under HSPs influence. Our review might showcase fresh potential for the development of next generation therapeutics for effective glioma management.
[Mh] Termos MeSH primário: Neoplasias Encefálicas/genética
Proteínas de Ligação a DNA/genética
Regulação Neoplásica da Expressão Gênica
Glioma/genética
Proteínas de Choque Térmico/genética
MicroRNAs/genética
Fatores de Transcrição/genética
[Mh] Termos MeSH secundário: Antineoplásicos/uso terapêutico
Neoplasias Encefálicas/patologia
Neoplasias Encefálicas/cirurgia
Neoplasias Encefálicas/terapia
Proteínas de Ligação a DNA/antagonistas & inibidores
Proteínas de Ligação a DNA/metabolismo
Progressão da Doença
Transição Epitelial-Mesenquimal/efeitos dos fármacos
Transição Epitelial-Mesenquimal/efeitos da radiação
Matriz Extracelular/efeitos dos fármacos
Matriz Extracelular/metabolismo
Matriz Extracelular/patologia
Matriz Extracelular/efeitos da radiação
Raios gama/uso terapêutico
Glioma/patologia
Glioma/cirurgia
Glioma/terapia
Fatores de Transcrição de Choque Térmico
Proteínas de Choque Térmico/antagonistas & inibidores
Proteínas de Choque Térmico/metabolismo
Seres Humanos
Lactamas Macrocíclicas/uso terapêutico
MicroRNAs/antagonistas & inibidores
MicroRNAs/metabolismo
Invasividade Neoplásica
Transdução de Sinais
Fatores de Transcrição/antagonistas & inibidores
Fatores de Transcrição/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (DNA-Binding Proteins); 0 (Heat Shock Transcription Factors); 0 (Heat-Shock Proteins); 0 (Lactams, Macrocyclic); 0 (MicroRNAs); 0 (Transcription Factors)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170829
[St] Status:MEDLINE


  8 / 2983 MEDLINE  
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[PMID]:28783748
[Au] Autor:Chatterjee S; Tatu U
[Ad] Endereço:Department of Biochemistry, Indian Institute of Science, Bangalore, India.
[Ti] Título:Heat shock protein 90 localizes to the surface and augments virulence factors of Cryptococcus neoformans.
[So] Source:PLoS Negl Trop Dis;11(8):e0005836, 2017 Aug.
[Is] ISSN:1935-2735
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Thermotolerance is an essential attribute for pathogenesis of Cryptococcus as exemplified by the fact that only two species in the genus, which can grow at 37°C, are human pathogens. Species which have other virulence factors including capsule formation and melanisation, but lack the ability to propagate at 37°C are not pathogenic. In another related fungal pathogen, Candida albicans, heat shock protein 90 has been implicated to be a central player in commanding pathogenicity by governing yeast to hyphal transition and drug resistance. Exploring Hsp90 biology in Cryptococcus in context of thermotolerance may thus highlight important regulatory principles of virulence and open new therapeutic avenues. METHODOLOGY/PRINCIPAL FINDINGS: Hsp90 is involved in regulating thermotolerance in Cryptococcus as indicated by growth hypersensitivity at 37°C upon mild compromise of Hsp90 function relative to 25°C. Biochemical studies revealed a more potent inhibition of ATPase activity by pharmacological inhibitor 17-AAG at 37°C as compared to 25°C. Catalytic efficiency of the protein at 37°C was found to be 6.39×10-5µM-1. Furthermore, indirect immunofluorescence analysis using a specific antibody revealed cell surface localization of Hsp90 via ER Golgi classical secretory pathway. Hsp90 was found to be induced under capsule inducing conditions and Hsp90 inhibition led to decrease in capsular volume. Finally compromising Hsp90 function improved anidulafungin tolerance in Cryptococcus. CONCLUSIONS/SIGNIFICANCE: Our findings highlight that Hsp90 regulates pathogenicity of the fungus by myriad ways. Firstly, it is involved in mediating thermotolerance which implies targeting Hsp90 can abrogate thermotolerance and hence growth of the fungus. Secondly, this study provides the first report of biochemical properties of Hsp90 of a pathogenic fungus. Finally, since Hsp90 is localised at the cell wall, targeting cell surface Hsp90 can represent a novel strategy to combat this lethal infection.
[Mh] Termos MeSH primário: Cryptococcus neoformans/patogenicidade
Proteínas Fúngicas/fisiologia
Proteínas de Choque Térmico HSP90/fisiologia
Fatores de Virulência/fisiologia
[Mh] Termos MeSH secundário: Benzoquinonas/farmacologia
Criptococose/microbiologia
Cryptococcus neoformans/efeitos dos fármacos
Equinocandinas/farmacologia
Seres Humanos
Lactamas Macrocíclicas/farmacologia
Testes de Sensibilidade Microbiana
Temperatura Ambiente
Termotolerância
Virulência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzoquinones); 0 (Echinocandins); 0 (Fungal Proteins); 0 (HSP90 Heat-Shock Proteins); 0 (Lactams, Macrocyclic); 0 (Virulence Factors); 4GY0AVT3L4 (tanespimycin); 9HLM53094I (anidulafungin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170827
[Lr] Data última revisão:
170827
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170808
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pntd.0005836


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[PMID]:28774796
[Au] Autor:Calero R; Morchon E; Martinez-Argudo I; Serrano R
[Ad] Endereço:Biochemistry Section, Faculty of Biochemistry and Environmental Sciences, University of Castilla-La Mancha, Toledo, Spain.
[Ti] Título:Synergistic anti-tumor effect of 17AAG with the PI3K/mTOR inhibitor NVP-BEZ235 on human melanoma.
[So] Source:Cancer Lett;406:1-11, 2017 Oct 10.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Drug resistance by MAPK signaling recovery or activation of alternative signaling pathways, such as PI3K/AKT/mTOR, is an important factor that limits the long-term efficacy of targeted therapies in melanoma patients. In the present study, we investigated the phospho-proteomic profile of RTKs and its correlation with downstream signaling pathways in human melanoma. We found that tyrosine kinase receptors expression correlated with the expression of pivotal downstream components of the RAS/RAF/MAPK and PI3K/AKT/mTOR pathways in melanoma cell lines and tumors. We also found high expression of HSP90 and the PI3K/AKT/mTOR pathway proteins, 4EBP1 and AKT compared with healthy tissue and this correlated with poor overall survival of melanoma patients. The combination of the HSP90 inhibitor 17AAG with the PI3K/mTOR inhibitor NVP-BEZ235 showed a synergistic activity decreasing melanoma cell growth, inducing apoptosis and targeting simultaneously the MAPK and PI3K/AKT/mTOR pathways. These results demonstrate that the combination of HSP90 and PI3K/mTOR inhibitors could be an effective therapeutic strategy that target the main survival pathways in melanoma and must be considered to overcome resistance to BRAF inhibitors in melanoma patients.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Benzoquinonas/farmacologia
Sinergismo Farmacológico
Imidazóis/farmacologia
Lactamas Macrocíclicas/farmacologia
Melanoma/tratamento farmacológico
Quinolinas/farmacologia
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Quimioterapia Combinada
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Proteínas de Choque Térmico HSP90/antagonistas & inibidores
Proteínas de Choque Térmico HSP90/metabolismo
Seres Humanos
Melanoma/metabolismo
Melanoma/patologia
Fosfatidilinositol 3-Quinases/antagonistas & inibidores
Fosfatidilinositol 3-Quinases/metabolismo
Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-akt/metabolismo
Pele/metabolismo
Serina-Treonina Quinases TOR/antagonistas & inibidores
Serina-Treonina Quinases TOR/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Benzoquinones); 0 (HSP90 Heat-Shock Proteins); 0 (Imidazoles); 0 (Lactams, Macrocyclic); 0 (Quinolines); 4GY0AVT3L4 (tanespimycin); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); RUJ6Z9Y0DT (dactolisib)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170921
[Lr] Data última revisão:
170921
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170805
[St] Status:MEDLINE


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[PMID]:28631426
[Au] Autor:Pennisi R; Antoccia A; Leone S; Ascenzi P; di Masi A
[Ad] Endereço:Department of Sciences, Roma Tre University, Roma, Italy.
[Ti] Título:Hsp90α regulates ATM and NBN functions in sensing and repair of DNA double-strand breaks.
[So] Source:FEBS J;284(15):2378-2395, 2017 Aug.
[Is] ISSN:1742-4658
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The molecular chaperone heat shock protein 90 (Hsp90α) regulates cell proteostasis and mitigates the harmful effects of endogenous and exogenous stressors on the proteome. Indeed, the inhibition of Hsp90α ATPase activity affects the cellular response to ionizing radiation (IR). Although the interplay between Hsp90α and several DNA damage response (DDR) proteins has been reported, its role in the DDR is still unclear. Here, we show that ataxia-telangiectasia-mutated kinase (ATM) and nibrin (NBN), but not 53BP1, RAD50, and MRE11, are Hsp90α clients as the Hsp90α inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) induces ATM and NBN polyubiquitination and proteosomal degradation in normal fibroblasts and lymphoblastoid cell lines. Hsp90α-ATM and Hsp90α-NBN complexes are present in unstressed and irradiated cells, allowing the maintenance of ATM and NBN stability that is required for the MRE11/RAD50/NBN complex-dependent ATM activation and the ATM-dependent phosphorylation of both NBN and Hsp90α in response to IR-induced DNA double-strand breaks (DSBs). Hsp90α forms a complex also with ph-Ser1981-ATM following IR. Upon phosphorylation, NBN dissociates from Hsp90α and translocates at the DSBs, while phThr5/7-Hsp90α is not recruited at the damaged sites. The inhibition of Hsp90α affects nuclear localization of MRE11 and RAD50, impairs DDR signaling (e.g., BRCA1 and CHK2 phosphorylation), and slows down DSBs repair. Hsp90α inhibition does not affect DNA-dependent protein kinase (DNA-PK) activity, which possibly phosphorylates Hsp90α and H2AX after IR. Notably, Hsp90α inhibition causes H2AX phosphorylation in proliferating cells, this possibly indicating replication stress events. Overall, present data shed light on the regulatory role of Hsp90α on the DDR, controlling ATM and NBN stability and influencing the DSBs signaling and repair.
[Mh] Termos MeSH primário: Proteínas Mutadas de Ataxia Telangiectasia/metabolismo
Proteínas de Ciclo Celular/metabolismo
Quebras de DNA de Cadeia Dupla
Reparo do DNA
Proteínas de Choque Térmico HSP90/metabolismo
Modelos Biológicos
Proteínas Nucleares/metabolismo
Processamento de Proteína Pós-Traducional
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores
Proteínas Mutadas de Ataxia Telangiectasia/química
Proteínas Mutadas de Ataxia Telangiectasia/genética
Benzoquinonas/farmacologia
Proteínas de Ciclo Celular/química
Proteínas de Ciclo Celular/genética
Linhagem Celular Transformada
Células Cultivadas
Quinase do Ponto de Checagem 1/química
Quinase do Ponto de Checagem 1/metabolismo
Quinase do Ponto de Checagem 2/química
Quinase do Ponto de Checagem 2/metabolismo
Reparo do DNA/efeitos dos fármacos
Deleção de Genes
Proteínas de Choque Térmico HSP90/antagonistas & inibidores
Proteínas de Choque Térmico HSP90/química
Seres Humanos
Lactamas Macrocíclicas/farmacologia
Síndrome de Quebra de Nijmegen/genética
Síndrome de Quebra de Nijmegen/metabolismo
Síndrome de Quebra de Nijmegen/patologia
Proteínas Nucleares/química
Proteínas Nucleares/genética
Fosforilação/efeitos dos fármacos
Mutação Puntual
Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos
Multimerização Proteica/efeitos dos fármacos
Processamento de Proteína Pós-Traducional/efeitos dos fármacos
Estabilidade Proteica/efeitos dos fármacos
Interferência de RNA
Ubiquitinação/efeitos dos fármacos
[Pt] Tipo de publicação:EDITORIAL
[Nm] Nome de substância:
0 (Benzoquinones); 0 (Cell Cycle Proteins); 0 (HSP90 Heat-Shock Proteins); 0 (HSP90AA1 protein, human); 0 (Lactams, Macrocyclic); 0 (NBN protein, human); 0 (Nuclear Proteins); 4GY0AVT3L4 (tanespimycin); EC 2.7.1.11 (Checkpoint Kinase 2); EC 2.7.11.1 (ATM protein, human); EC 2.7.11.1 (ATR protein, human); EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins); EC 2.7.11.1 (CHEK1 protein, human); EC 2.7.11.1 (CHEK2 protein, human); EC 2.7.11.1 (Checkpoint Kinase 1); EC 3.4.25.1 (Proteasome Endopeptidase Complex)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171120
[Lr] Data última revisão:
171120
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170621
[St] Status:MEDLINE
[do] DOI:10.1111/febs.14145



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