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[PMID]:27245608
[Au] Autor:Fields AP; Ali SA; Justilien V; Murray NR
[Ad] Endereço:a Department of Cancer Biology , Mayo Clinic , Jacksonville , FL , USA.
[Ti] Título:Targeting oncogenic protein kinase Cι for treatment of mutant KRAS LADC.
[So] Source:Small GTPases;8(1):58-64, 2017 Jan 02.
[Is] ISSN:2154-1256
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Lung cancer is the leading cause of cancer death in the US with ∼124,000 new cases annually, and a 5 y survival rate of ∼16%. Mutant KRAS-driven lung adenocarcinoma (KRAS LADC) is a particularly prevalent and deadly form of lung cancer. Protein kinase Cι (PKCι) is an oncogenic effector of KRAS that activates multiple signaling pathways that stimulate transformed growth and invasion, and maintain a KRAS LADC tumor-initiating cell (TIC) phenotype. PKCι inhibitors used alone and in strategic combination show promise as new therapeutic approaches to treatment of KRAS LADC. These novel drug combinations may improve clinical management of KRAS LADC.
[Mh] Termos MeSH primário: Tiomalato Sódico de Ouro/administração & dosagem
Isoenzimas/metabolismo
Neoplasias Pulmonares/tratamento farmacológico
Proteína Quinase C/metabolismo
Proteínas Proto-Oncogênicas p21(ras)/genética
Sirolimo/administração & dosagem
[Mh] Termos MeSH secundário: Células A549
Animais
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Linhagem Celular Tumoral
Tiomalato Sódico de Ouro/farmacologia
Seres Humanos
Neoplasias Pulmonares/genética
Neoplasias Pulmonares/metabolismo
Camundongos
Mutação
Células-Tronco Neoplásicas/efeitos dos fármacos
Sirolimo/farmacologia
Resultado do Tratamento
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Isoenzymes); 0 (KRAS protein, human); 12244-57-4 (Gold Sodium Thiomalate); EC 2.7.11.13 (Protein Kinase C); EC 2.7.11.13 (protein kinase C lambda); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)); W36ZG6FT64 (Sirolimus)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160602
[St] Status:MEDLINE
[do] DOI:10.1080/21541248.2016.1194953


  2 / 1254 MEDLINE  
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[PMID]:25915428
[Au] Autor:Butler AM; Scotti Buzhardt ML; Erdogan E; Li S; Inman KS; Fields AP; Murray NR
[Ad] Endereço:Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
[Ti] Título:A small molecule inhibitor of atypical protein kinase C signaling inhibits pancreatic cancer cell transformed growth and invasion.
[So] Source:Oncotarget;6(17):15297-310, 2015 Jun 20.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pancreatic cancer is highly resistant to current chemotherapies. Identification of the critical signaling pathways that mediate pancreatic cancer transformed growth is necessary for the development of more effective therapeutic treatments. Recently, we demonstrated that protein kinase C iota (PKCι) and zeta (PKCζ) promote pancreatic cancer transformed growth and invasion, by activating Rac1→ERK and STAT3 signaling pathways, respectively. However, a key question is whether PKCι and PKCζ play redundant (or non-redundant) roles in pancreatic cancer cell transformed growth. Here we describe the novel observations that 1) PKCι and PKCζ are non-redundant in the context of the transformed growth of pancreatic cancer cells; 2) a gold-containing small molecule known to disrupt the PKCι/Par6 interaction, aurothiomalate, also disrupts PKCζ/Par6 interaction; 3) aurothiomalate inhibits downstream signaling of both PKCι and PKCζ, and blocks transformed growth of pancreatic cancer cells in vitro; and 4) aurothiomalate inhibits pancreatic cancer tumor growth and metastasis in vivo. Taken together, these data provide convincing evidence that an inhibitor of atypical PKC signaling inhibits two key oncogenic signaling pathways, driven non-redundantly by PKCι and PKCζ, to significantly reduce tumor growth and metastasis. Our results demonstrate that inhibition of atypical PKC signaling is a promising therapeutic strategy to treat pancreatic cancer.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Tiomalato Sódico de Ouro/farmacologia
Isoenzimas/antagonistas & inibidores
Neoplasias Pancreáticas/patologia
Proteína Quinase C/antagonistas & inibidores
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/genética
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Transformação Celular Neoplásica/efeitos dos fármacos
Transformação Celular Neoplásica/patologia
Seres Humanos
Isoenzimas/genética
Invasividade Neoplásica/patologia
Ligação Proteica
Proteína Quinase C/genética
Proteína Quinase C/metabolismo
Interferência de RNA
RNA Interferente Pequeno
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Isoenzymes); 0 (PARD6A protein, human); 0 (RNA, Small Interfering); 12244-57-4 (Gold Sodium Thiomalate); EC 2.7.11.1 (protein kinase C zeta); EC 2.7.11.13 (Protein Kinase C); EC 2.7.11.13 (protein kinase C lambda)
[Em] Mês de entrada:1604
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150428
[St] Status:MEDLINE


  3 / 1254 MEDLINE  
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[PMID]:25865000
[Au] Autor:Darabi F; Marzo T; Massai L; Scaletti F; Michelucci E; Messori L
[Ad] Endereço:Department of Chemistry, Isfahan University of Technology, Isfahan 84156-83111, Iran; Laboratory of Metals in Medicine, Department of Chemistry, University of Florence, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
[Ti] Título:Reactions of model proteins with aurothiomalate, a clinically established gold(I) drug: The comparison with auranofin.
[So] Source:J Inorg Biochem;149:102-7, 2015 Aug.
[Is] ISSN:1873-3344
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Aurothiomalate (AuTm) is an old, clinically established, antiarthritic gold drug that is currently being reconsidered as a candidate drug for cancer treatment and for other therapeutic indications within a more general drug repositioning program. As the biological effects of gold drugs seem to be mediated, mainly, by their interactions with protein targets we have analyzed here, in detail, the metalation patterns produced by aurothiomalate in a few model proteins. In particular, the reactions of aurothiomalate with the small proteins ribonuclease A, cytochrome c and lysozyme were explored through ESI MS (electrospray ionization mass spectrometry) analysis. Notably, characteristic and rather constant features emerged in the protein metalation patterns induced by AuTm that are markedly distinct from those caused by auranofin; a non-covalent interaction mode is invoked for AuTm binding to the mentioned proteins. The affinity constants of AuTm toward the three mentioned proteins were also initially assessed. The implications of the present findings are discussed.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Auranofina/farmacologia
Citocromos c/metabolismo
Tiomalato Sódico de Ouro/farmacologia
Muramidase/metabolismo
Ribonuclease Pancreático/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Antineoplásicos/química
Auranofina/química
Sítios de Ligação
Citocromos c/química
Tiomalato Sódico de Ouro/química
Dados de Sequência Molecular
Muramidase/química
Ligação Proteica
Ribonuclease Pancreático/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 12244-57-4 (Gold Sodium Thiomalate); 3H04W2810V (Auranofin); 9007-43-6 (Cytochromes c); EC 3.1.27.5 (Ribonuclease, Pancreatic); EC 3.2.1.17 (Muramidase)
[Em] Mês de entrada:1603
[Cu] Atualização por classe:150615
[Lr] Data última revisão:
150615
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150414
[St] Status:MEDLINE


  4 / 1254 MEDLINE  
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[PMID]:25778647
[Au] Autor:Zyuz'kov GN; Zhdanov VV; Udut EV; Miroshnichenko LA; Chaikovskii AV; Simanina EV; Danilets MG; Minakova MY; Demkin VP; Udut VV; Tolstikova TG; Shults EE; Agafonov VI; Dygai AM
[Ad] Endereço:E. D. Goldberg Research Institute of Pharmacology, Siberian Division of the Russian Academy of Medical Sciences, Tomsk, Russia, zgn@pharm.tsu.ru.
[Ti] Título:Role of NF-κB/IKK-dependent signaling in functional stimulation of mesenchymal progenitor cells by alkaloid songorine.
[So] Source:Bull Exp Biol Med;158(5):624-7, 2015 Mar.
[Is] ISSN:1573-8221
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We studied the role of NF-κB/IKK-mediated signaling in the stimulation of growth potential of mesenchymal progenitor cells by alkaloid songorine in vitro. Specific NF-κB inhibitor oridonin abolished activation of proliferation and differentiation of progenitor cells. Aurothiomalate, a selective blocker of IKK-2, also suppressed mitotic activity of fibroblast precursors, but had no effect on the rate of the differentiation.
[Mh] Termos MeSH primário: Alcaloides/farmacologia
Quinase I-kappa B/metabolismo
Células Mesenquimais Estromais/efeitos dos fármacos
Células Mesenquimais Estromais/metabolismo
NF-kappa B/metabolismo
[Mh] Termos MeSH secundário: Animais
Diferenciação Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Células Cultivadas
Diterpenos Caurânicos/farmacologia
Tiomalato Sódico de Ouro/farmacologia
Quinase I-kappa B/antagonistas & inibidores
Camundongos
Modelos Biológicos
NF-kappa B/antagonistas & inibidores
Medicina Regenerativa
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Alkaloids); 0 (Diterpenes, Kaurane); 0 (NF-kappa B); 0APJ98UCLQ (oridonin); 12244-57-4 (Gold Sodium Thiomalate); 64E5D8C741 (songorine); EC 2.7.11.10 (I-kappa B Kinase); EC 2.7.11.10 (Ikbkb protein, mouse)
[Em] Mês de entrada:1601
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150318
[St] Status:MEDLINE
[do] DOI:10.1007/s10517-015-2822-z


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[PMID]:25314295
[Au] Autor:Tuure L; Hämäläinen M; Moilanen T; Moilanen E
[Ad] Endereço:The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital , Tampere , Finland.
[Ti] Título:Aurothiomalate inhibits the expression of mPGES-1 in primary human chondrocytes.
[So] Source:Scand J Rheumatol;44(1):74-9, 2015.
[Is] ISSN:1502-7732
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: Microsomal prostaglandin E synthase-1 (mPGES-1) is a terminal enzyme in the production of prostaglandin E2 (PGE2) and its expression is upregulated during inflammation. mPGES-1 is considered as a potential drug target for the treatment of arthritis to reduce adverse effects related to the current non-steroidal anti-inflammatory drugs (NSAIDs). Our aim was to study the expression of mPGES-1 in primary human chondrocytes and whether the expression is affected by clinically used antirheumatic drugs. METHOD: Primary human chondrocytes were isolated from cartilage samples obtained from patients undergoing total knee replacement surgery. Expression of mPGES-1 was studied by quantitative real-time polymerase chain reaction (PCR) and Western blot analysis. PGE2 levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: mPGES-1 expression in primary human chondrocytes was enhanced when the cells were exposed to interleukin-1ß (IL-1ß) and mPGES-1 protein levels continued to increase up to the 96-h follow-up. Aurothiomalate inhibited mPGES-1 expression and PGE2 production in a dose-dependent manner, as did the anti-inflammatory steroid dexamethasone. Other disease-modifying antirheumatic drugs (DMARDs) studied (sulfasalazine, methotrexate, and hydroxychloroquine) did not alter mPGES-1 expression. CONCLUSIONS: The results introduce aurothiomalate as the first, and so far the only, DMARD found to be able to inhibit mPGES-1 expression. The effect is likely involved in the mechanisms of action of this gold-containing DMARD in rheumatic diseases. The results are implicated in the regulatory mechanisms of mPGES-1 expression, which are under intensive research.
[Mh] Termos MeSH primário: Antirreumáticos/farmacologia
Condrócitos/efeitos dos fármacos
Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos
Tiomalato Sódico de Ouro/farmacologia
Oxirredutases Intramoleculares/genética
[Mh] Termos MeSH secundário: Condrócitos/citologia
Condrócitos/fisiologia
Dexametasona/farmacologia
Dinoprostona/biossíntese
Ensaio de Imunoadsorção Enzimática
Glucocorticoides/farmacologia
Seres Humanos
Hidroxicloroquina/farmacologia
Oxirredutases Intramoleculares/metabolismo
Metotrexato/farmacologia
Osteoartrite do Joelho/tratamento farmacológico
Cultura Primária de Células
Prostaglandina-E Sintases
Reação em Cadeia da Polimerase em Tempo Real
Sulfassalazina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antirheumatic Agents); 0 (Glucocorticoids); 12244-57-4 (Gold Sodium Thiomalate); 3XC8GUZ6CB (Sulfasalazine); 4QWG6N8QKH (Hydroxychloroquine); 7S5I7G3JQL (Dexamethasone); EC 5.3.- (Intramolecular Oxidoreductases); EC 5.3.99.3 (PTGES protein, human); EC 5.3.99.3 (Prostaglandin-E Synthases); K7Q1JQR04M (Dinoprostone); YL5FZ2Y5U1 (Methotrexate)
[Em] Mês de entrada:1503
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141015
[St] Status:MEDLINE
[do] DOI:10.3109/03009742.2014.927917


  6 / 1254 MEDLINE  
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[PMID]:25306263
[Au] Autor:James LR; Xu ZQ; Sluyter R; Hawksworth EL; Kelso C; Lai B; Paterson DJ; de Jonge MD; Dixon NE; Beck JL; Ralph SF; Dillon CT
[Ad] Endereço:Centre for Medical and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia; School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia.
[Ti] Título:An investigation into the interactions of gold nanoparticles and anti-arthritic drugs with macrophages, and their reactivity towards thioredoxin reductase.
[So] Source:J Inorg Biochem;142:28-38, 2015 Jan.
[Is] ISSN:1873-3344
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Gold(I) complexes are an important tool in the arsenal of established approaches for treating rheumatoid arthritis (RA), while some recent studies have suggested that gold nanoparticles (Au NPs) may also be therapeutically efficacious. These observations prompted the current biological studies involving gold(I) anti-RA agents and Au NPs, which are aimed towards improving our knowledge of how they work. The cytotoxicity of auranofin, aurothiomalate, aurothiosulfate and Au NPs towards RAW264.7 macrophages was evaluated using the MTT assay, with the former compound proving to be the most toxic. The extent of cellular uptake of the various gold agents was determined using graphite furnace atomic absorption spectrometry, while their distribution within macrophages was examined using microprobe synchrotron radiation X-ray fluorescence spectroscopy. The latter technique showed accumulation of gold in discrete regions of the cell, and co-localisation with sulfur in the case of cells treated with aurothiomalate or auranofin. Electrospray ionization mass spectrometry was used to characterize thioredoxin reductase (TrxR) in which the penultimate selenocysteine residue was replaced by cysteine. Mass spectra of solutions of TrxR and aurothiomalate, aurothiosulfate or auranofin showed complexes containing bare gold atoms bound to the protein, or protein adducts containing gold atoms retaining some of their initial ligands. These results support TrxR being an important target of gold(I) drugs used to treat RA, while the finding that Au NPs are incorporated into macrophages, but elicit little toxicity, indicates further exploration of their potential for treatment of RA is warranted.
[Mh] Termos MeSH primário: Ouro
Macrófagos/efeitos dos fármacos
Nanopartículas Metálicas/toxicidade
Tiorredoxina Dissulfeto Redutase/metabolismo
[Mh] Termos MeSH secundário: Auranofina/metabolismo
Auranofina/toxicidade
Ouro/análise
Tiomalato Sódico de Ouro/metabolismo
Tiomalato Sódico de Ouro/toxicidade
Macrófagos/metabolismo
Espectrometria de Massas por Ionização por Electrospray/métodos
Espectrometria por Raios X/métodos
Espectrofotometria Atômica/métodos
Tiorredoxina Dissulfeto Redutase/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
12244-57-4 (Gold Sodium Thiomalate); 3H04W2810V (Auranofin); 7440-57-5 (Gold); EC 1.8.1.9 (Thioredoxin-Disulfide Reductase)
[Em] Mês de entrada:1507
[Cu] Atualização por classe:141201
[Lr] Data última revisão:
141201
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141013
[St] Status:MEDLINE


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[PMID]:24915945
[Au] Autor:Dygai AM; Zhdanov VV; Zyuz'kov GN; Udut EV; Miroshnichenko LA; Simanina EV; Chaikovskii AV; Stavrova LA; Danilets MG
[Ad] Endereço:Research Institute of Pharmacology, Siberian Division of the Russian Academy of Sciences, Tomsk, Russia, digay_am@pharmso.ru.
[Ti] Título:Role of NF-κB-dependent signaling and p38 MAPK signaling pathway in the control of hemopoiesis during cytostatic administration.
[So] Source:Bull Exp Biol Med;157(1):32-6, 2014 May.
[Is] ISSN:1573-8221
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The study examines the role of signal pathways in triggering the compensatory reactions in the blood system in response to the cytostatic administration. In vitro experiments elucidated the involvement of protein kinase p38 in the synthesis of granulocytic CSF by cells of hemopoietic microenvironment. The important role of the transcriptional factor NF-κB and protein kinase p38 in limitation of the processes of maturation of the hemopoietic precursors was demonstrated.
[Mh] Termos MeSH primário: Células da Medula Óssea/metabolismo
Ciclofosfamida/farmacologia
Agonistas Mieloablativos/farmacologia
NF-kappa B/metabolismo
Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
[Mh] Termos MeSH secundário: Animais
Células da Medula Óssea/efeitos dos fármacos
Células da Medula Óssea/patologia
Diferenciação Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Inibidores Enzimáticos/farmacologia
Células Eritroides/efeitos dos fármacos
Células Eritroides/metabolismo
Células Eritroides/patologia
Regulação da Expressão Gênica
Tiomalato Sódico de Ouro/farmacologia
Fator Estimulador de Colônias de Granulócitos/biossíntese
Fator Estimulador de Colônias de Granulócitos/secreção
Granulócitos/efeitos dos fármacos
Granulócitos/metabolismo
Granulócitos/patologia
Hematopoese/efeitos dos fármacos
Imidazóis/farmacologia
Injeções Intraperitoneais
Masculino
Camundongos
Camundongos Endogâmicos CBA
NF-kappa B/antagonistas & inibidores
NF-kappa B/genética
Cultura Primária de Células
Piridinas/farmacologia
Transdução de Sinais
Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
Proteínas Quinases p38 Ativadas por Mitógeno/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Imidazoles); 0 (Myeloablative Agonists); 0 (NF-kappa B); 0 (Pyridines); 12244-57-4 (Gold Sodium Thiomalate); 143011-72-7 (Granulocyte Colony-Stimulating Factor); 8N3DW7272P (Cyclophosphamide); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases); OU13V1EYWQ (SB 203580)
[Em] Mês de entrada:1502
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140612
[St] Status:MEDLINE
[do] DOI:10.1007/s10517-014-2485-1


  8 / 1254 MEDLINE  
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[PMID]:24651432
[Au] Autor:Ma CQ; Yang Y; Wang JM; Du GS; Shen Q; Liu Y; Zhang J; Hu JL; Zhu P; Qi WP; Qian YW; Fu Y
[Ad] Endereço:Department of Biliary and Pancreatic Surgery/Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
[Ti] Título:The aPKCι blocking agent ATM negatively regulates EMT and invasion of hepatocellular carcinoma.
[So] Source:Cell Death Dis;5:e1129, 2014 Mar 20.
[Is] ISSN:2041-4889
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Epithelial-to-mesenchymal transition (EMT) has an important role in invasion and metastasis of hepatocellular carcinoma (HCC). To explore the regulatory mechanism of atypical protein kinase C ι (aPKCι) signaling pathways to HCC development, and find an agent for targeted therapy for HCC, immortalized murine hepatocytes were employed to establish an EMT cell model of HCC, MMH-RT cells. Our study showed that EMT took place in MMH-R cells under the effect of transforming growth factor-ß1 (TGF-ß1) overexpressing aPKCι. Furthermore, we showed that the aPKCι blocking agent aurothiomalate (ATM) inhibited EMT and decreased invasion of hepatocytes. Moreover, ATM selectively inhibited proliferation of mesenchymal cells and HepG2 cells and induced apoptosis. However, ATM increased proliferation of epithelial cells and had little effect on apoptosis and invasion of epithelial cells. In conclusion, our result suggested that aPKCι could be an important bio-marker of tumor EMT, and used as an indicator of invasion and malignancy. ATM might be a promising agent for targeted treatment of HCC.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Biomarcadores Tumorais/antagonistas & inibidores
Carcinoma Hepatocelular/enzimologia
Movimento Celular/efeitos dos fármacos
Transição Epitelial-Mesenquimal/efeitos dos fármacos
Tiomalato Sódico de Ouro/farmacologia
Isoenzimas/antagonistas & inibidores
Neoplasias Hepáticas/enzimologia
Proteína Quinase C/antagonistas & inibidores
Inibidores de Proteínas Quinases/farmacologia
[Mh] Termos MeSH secundário: Animais
Apoptose/efeitos dos fármacos
Biomarcadores Tumorais/metabolismo
Carcinoma Hepatocelular/genética
Carcinoma Hepatocelular/patologia
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Genes ras
Células Hep G2
Seres Humanos
Isoenzimas/genética
Isoenzimas/metabolismo
Neoplasias Hepáticas/genética
Neoplasias Hepáticas/patologia
Camundongos
Invasividade Neoplásica
Proteína Quinase C/genética
Proteína Quinase C/metabolismo
Transdução de Sinais/efeitos dos fármacos
Fatores de Tempo
Transfecção
Fator de Crescimento Transformador beta1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Biomarkers, Tumor); 0 (Isoenzymes); 0 (Protein Kinase Inhibitors); 0 (TGFB1 protein, human); 0 (Transforming Growth Factor beta1); 12244-57-4 (Gold Sodium Thiomalate); EC 2.7.11.13 (Protein Kinase C); EC 2.7.11.13 (protein kinase C lambda)
[Em] Mês de entrada:1410
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140322
[St] Status:MEDLINE
[do] DOI:10.1038/cddis.2014.91


  9 / 1254 MEDLINE  
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[PMID]:24304691
[Au] Autor:Scharf VF; Farese JP; Siemann DW; Abbott JR; Kiupel M; Salute ME; Milner RJ
[Ad] Endereço:Departments of aSmall Animal Clinical Sciences bInfectious Diseases and Pathology, College of Veterinary Medicine cDepartment of Radiation Oncology, College of Medicine, University of Florida, Gainesville, Florida dVCA Animal Care Center of Sonoma County, Rohnert Park, California eDepartment of Pathobiology and Diagnostic Investigation, Michigan State University, Lansing, Michigan, USA.
[Ti] Título:Effects of aurothiomalate treatment on canine osteosarcoma in a murine xenograft model.
[So] Source:Anticancer Drugs;25(3):332-9, 2014 Mar.
[Is] ISSN:1473-5741
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Osteosarcoma is a highly fatal cancer, with most patients ultimately succumbing to metastatic disease. The purpose of this study was to evaluate the effects of the antirheumatoid drug aurothiomalate on canine and human osteosarcoma cells and on canine osteosarcoma growth and metastasis in a mouse xenograft model. We hypothesized that aurothiomalate would decrease osteosarcoma cell survival, tumor cellular proliferation, tumor growth, and metastasis. After performing clonogenic assays, aurothiomalate or a placebo was administered to 54 mice inoculated with canine osteosarcoma. Survival, tumor growth, embolization, metastasis, histopathology, cell proliferation marker Ki67, and apoptosis marker caspase-3 were compared between groups. Statistical analysis was carried out using the Kaplan-Meier method with the log-rank test and one-way analysis of variance with the Tukey's test or Dunn's method. Aurothiomalate caused dose-dependent inhibition of osteosarcoma cell survival (P<0.001) and decreased tumor growth (P<0.001). Pulmonary macrometastasis and Ki67 labeling were reduced with low-dose aurothiomalate (P=0.033 and 0.005, respectively), and tumor emboli and pulmonary micrometastases were decreased with high-dose aurothiomalate (P=0.010 and 0.011, respectively). There was no difference in survival, tumor development, ulceration, mitotic indices, tumor necrosis, nonpulmonary metastases, and caspase-3 labeling. Aurothiomalate treatment inhibited osteosarcoma cell survival and reduced tumor cell proliferation, growth, embolization, and pulmonary metastasis. Given aurothiomalate's established utility in canine and human medicine, our results suggest that this compound may hold promise as an adjunctive therapy for osteosarcoma. Further translational research is warranted to better characterize the dose response of canine and human osteosarcoma to aurothiomalate.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Neoplasias Ósseas/tratamento farmacológico
Tiomalato Sódico de Ouro/uso terapêutico
Osteossarcoma/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/farmacologia
Apoptose/efeitos dos fármacos
Neoplasias Ósseas/patologia
Caspase 3/metabolismo
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Cães
Tiomalato Sódico de Ouro/farmacologia
Seres Humanos
Antígeno Ki-67/metabolismo
Neoplasias Pulmonares/tratamento farmacológico
Neoplasias Pulmonares/secundário
Camundongos
Osteossarcoma/patologia
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Ki-67 Antigen); 12244-57-4 (Gold Sodium Thiomalate); EC 3.4.22.- (Caspase 3)
[Em] Mês de entrada:1408
[Cu] Atualização por classe:140124
[Lr] Data última revisão:
140124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:131206
[St] Status:MEDLINE
[do] DOI:10.1097/CAD.0000000000000061


  10 / 1254 MEDLINE  
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[PMID]:23962904
[Au] Autor:Mansfield AS; Fields AP; Jatoi A; Qi Y; Adjei AA; Erlichman C; Molina JR
[Ad] Endereço:aDepartment of Medical Oncology, Mayo Clinic, Rochester, Minnesota bDepartment of Cancer Biology, Mayo Clinic, Jacksonville, Florida cDepartment of Internal Medicine, Greater Baltimore Medical Center, Baltimore, Maryland dDepartment of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA.
[Ti] Título:Phase I dose escalation study of the PKCι inhibitor aurothiomalate for advanced non-small-cell lung cancer, ovarian cancer, and pancreatic cancer.
[So] Source:Anticancer Drugs;24(10):1079-83, 2013 Nov.
[Is] ISSN:1473-5741
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Protein kinase C iota (PKCι) is overexpressed in non-small-cell lung cancer, ovarian, and pancreatic cancers, where it plays a critical role in oncogenesis. The gold compound aurothiomalate (ATM) has been shown to inhibit PKCι signaling and exerts potent antitumor activity in preclinical models. We sought to determine the maximum tolerated dose (MTD) of ATM. We conducted a phase I dose escalation trial of ATM in patients with non-small-cell lung cancer, ovarian or pancreatic cancer. Patients received ATM intramuscularly weekly for three cycles (cycle duration 4 weeks) at 25, 50, or 75 mg in a 3+3 design. The dose was not escalated for individual patients. Blood samples were analyzed for elemental gold levels. Patients were evaluated every 4 weeks for toxicity and every 8 weeks for response. Fifteen patients were enrolled in this study. Six patients were treated at 25 mg, seven at 50 mg, and two at 75 mg. There was one dose-limiting toxicity at 25 mg (hypokalemia), one at 50 mg (urinary tract infection), and none at 75 mg. There were three grade 3 hematologic toxicities. The recommended MTD of ATM is 50 mg. Patients received treatment for a median of two cycles (range 1-3). There appeared to be a dose-related accumulation of steady-state plasma concentrations of gold consistent with linear pharmacokinetics. In summary, this phase I study was successful in identifying ATM 50 mg intramuscularly weekly as the MTD. Future clinical investigations targeting PKCι are currently in progress.
[Mh] Termos MeSH primário: Antineoplásicos/administração & dosagem
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico
Tiomalato Sódico de Ouro/administração & dosagem
Isoenzimas/antagonistas & inibidores
Neoplasias Pulmonares/tratamento farmacológico
Neoplasias Ovarianas/tratamento farmacológico
Neoplasias Pancreáticas/tratamento farmacológico
Proteína Quinase C/antagonistas & inibidores
[Mh] Termos MeSH secundário: Idoso
Antineoplásicos/farmacocinética
Antineoplásicos/uso terapêutico
Antineoplásicos/toxicidade
Carcinoma Pulmonar de Células não Pequenas/enzimologia
Relação Dose-Resposta a Droga
Feminino
Ouro/sangue
Tiomalato Sódico de Ouro/farmacocinética
Tiomalato Sódico de Ouro/uso terapêutico
Tiomalato Sódico de Ouro/toxicidade
Seres Humanos
Injeções Intramusculares
Neoplasias Pulmonares/enzimologia
Masculino
Meia-Idade
Neoplasias Ovarianas/enzimologia
Neoplasias Pancreáticas/enzimologia
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Isoenzymes); 12244-57-4 (Gold Sodium Thiomalate); 7440-57-5 (Gold); EC 2.7.11.13 (Protein Kinase C); EC 2.7.11.13 (protein kinase C lambda)
[Em] Mês de entrada:1405
[Cu] Atualização por classe:161203
[Lr] Data última revisão:
161203
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130822
[St] Status:MEDLINE
[do] DOI:10.1097/CAD.0000000000000009



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