Database : MEDLINE
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  1 / 1254 MEDLINE  
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PMID:27245608
Author:Fields AP; Ali SA; Justilien V; Murray NR
Address:a Department of Cancer Biology , Mayo Clinic , Jacksonville , FL , USA.
Title:Targeting oncogenic protein kinase Cι for treatment of mutant KRAS LADC.
Source:Small GTPases; 8(1):58-64, 2017 Jan 02.
ISSN:2154-1256
Country of publication:United States
Language:eng
Abstract: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.
Publication type:JOURNAL ARTICLE
Name of substance: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)


  2 / 1254 MEDLINE  
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PMID:25915428
Author:Butler AM; Scotti Buzhardt ML; Erdogan E; Li S; Inman KS; Fields AP; Murray NR
Address:Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
Title:A small molecule inhibitor of atypical protein kinase C signaling inhibits pancreatic cancer cell transformed growth and invasion.
Source:Oncotarget; 6(17):15297-310, 2015 Jun 20.
ISSN:1949-2553
Country of publication:United States
Language:eng
Abstract: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.
Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
Name of substance: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)


  3 / 1254 MEDLINE  
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PMID:25865000
Author:Darabi F; Marzo T; Massai L; Scaletti F; Michelucci E; Messori L
Address: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.
Title:Reactions of model proteins with aurothiomalate, a clinically established gold(I) drug: The comparison with auranofin.
Source:J Inorg Biochem; 149:102-7, 2015 Aug.
ISSN:1873-3344
Country of publication:United States
Language:eng
Abstract: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.
Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
Name of substance: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)


  4 / 1254 MEDLINE  
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PMID:25778647
Author: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
Address:E. D. Goldberg Research Institute of Pharmacology, Siberian Division of the Russian Academy of Medical Sciences, Tomsk, Russia, zgn@pharm.tsu.ru.
Title:Role of NF-κB/IKK-dependent signaling in functional stimulation of mesenchymal progenitor cells by alkaloid songorine.
Source:Bull Exp Biol Med; 158(5):624-7, 2015 Mar.
ISSN:1573-8221
Country of publication:United States
Language:eng
Abstract: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.
Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
Name of substance: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)


  5 / 1254 MEDLINE  
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PMID:25314295
Author:Tuure L; Hämäläinen M; Moilanen T; Moilanen E
Address:The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital , Tampere , Finland.
Title:Aurothiomalate inhibits the expression of mPGES-1 in primary human chondrocytes.
Source:Scand J Rheumatol; 44(1):74-9, 2015.
ISSN:1502-7732
Country of publication:England
Language:eng
Abstract: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.
Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
Name of substance: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)


  6 / 1254 MEDLINE  
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PMID:25306263
Author: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
Address:Centre for Medical and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia; School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia.
Title:An investigation into the interactions of gold nanoparticles and anti-arthritic drugs with macrophages, and their reactivity towards thioredoxin reductase.
Source:J Inorg Biochem; 142:28-38, 2015 Jan.
ISSN:1873-3344
Country of publication:United States
Language:eng
Abstract: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.
Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
Name of substance:12244-57-4 (Gold Sodium Thiomalate); 3H04W2810V (Auranofin); 7440-57-5 (Gold); EC 1.8.1.9 (Thioredoxin-Disulfide Reductase)


  7 / 1254 MEDLINE  
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PMID:24915945
Author:Dygai AM; Zhdanov VV; Zyuz'kov GN; Udut EV; Miroshnichenko LA; Simanina EV; Chaikovskii AV; Stavrova LA; Danilets MG
Address:Research Institute of Pharmacology, Siberian Division of the Russian Academy of Sciences, Tomsk, Russia, digay_am@pharmso.ru.
Title:Role of NF-κB-dependent signaling and p38 MAPK signaling pathway in the control of hemopoiesis during cytostatic administration.
Source:Bull Exp Biol Med; 157(1):32-6, 2014 May.
ISSN:1573-8221
Country of publication:United States
Language:eng
Abstract: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.
Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
Name of substance: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)


  8 / 1254 MEDLINE  
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PMID:24651432
Author:Ma CQ; Yang Y; Wang JM; Du GS; Shen Q; Liu Y; Zhang J; Hu JL; Zhu P; Qi WP; Qian YW; Fu Y
Address:Department of Biliary and Pancreatic Surgery/Cancer Research Center Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Title:The aPKCι blocking agent ATM negatively regulates EMT and invasion of hepatocellular carcinoma.
Source:Cell Death Dis; 5:e1129, 2014 Mar 20.
ISSN:2041-4889
Country of publication:England
Language:eng
Abstract: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.
Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
Name of substance: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)


  9 / 1254 MEDLINE  
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PMID:24304691
Author:Scharf VF; Farese JP; Siemann DW; Abbott JR; Kiupel M; Salute ME; Milner RJ
Address: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.
Title:Effects of aurothiomalate treatment on canine osteosarcoma in a murine xenograft model.
Source:Anticancer Drugs; 25(3):332-9, 2014 Mar.
ISSN:1473-5741
Country of publication:England
Language:eng
Abstract: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.
Publication type:JOURNAL ARTICLE
Name of substance:0 (Antineoplastic Agents); 0 (Ki-67 Antigen); 12244-57-4 (Gold Sodium Thiomalate); EC 3.4.22.- (Caspase 3)


  10 / 1254 MEDLINE  
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PMID:23962904
Author:Mansfield AS; Fields AP; Jatoi A; Qi Y; Adjei AA; Erlichman C; Molina JR
Address: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.
Title:Phase I dose escalation study of the PKCι inhibitor aurothiomalate for advanced non-small-cell lung cancer, ovarian cancer, and pancreatic cancer.
Source:Anticancer Drugs; 24(10):1079-83, 2013 Nov.
ISSN:1473-5741
Country of publication:England
Language:eng
Abstract: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.
Publication type:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
Name of substance: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)



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