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[PMID]:29402888
[Au] Autor:Yano H; Cai NS; Xu M; Verma RK; Rea W; Hoffman AF; Shi L; Javitch JA; Bonci A; Ferré S
[Ad] Endereço:National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA. hideaki.yano@nih.gov.
[Ti] Título:Gs- versus Golf-dependent functional selectivity mediated by the dopamine D receptor.
[So] Source:Nat Commun;9(1):486, 2018 02 05.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The two highly homologous subtypes of stimulatory G proteins Gαs (Gs) and Gαolf (Golf) display contrasting expression patterns in the brain. Golf is predominant in the striatum, while Gs is predominant in the cortex. Yet, little is known about their functional distinctions. The dopamine D receptor (D1R) couples to Gs/olf and is highly expressed in cortical and striatal areas, making it an important therapeutic target for neuropsychiatric disorders. Using novel drug screening methods that allow analysis of specific G-protein subtype coupling, we found that, relative to dopamine, dihydrexidine and N-propyl-apomorphine behave as full D1R agonists when coupled to Gs, but as partial D1R agonists when coupled to Golf. The Gs/Golf-dependent biased agonism by dihydrexidine was consistently observed at the levels of cellular signaling, neuronal function, and behavior. Our findings of Gs/Golf-dependent functional selectivity in D1R ligands open a new avenue for the treatment of cortex-specific or striatum-specific neuropsychiatric dysfunction.
[Mh] Termos MeSH primário: Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo
Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo
Fenantridinas/farmacologia
Receptores de Dopamina D1/agonistas
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Sítios de Ligação
Encéfalo/metabolismo
Linhagem Celular Tumoral
Subunidades alfa de Proteínas de Ligação ao GTP/genética
Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética
Regulação da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Camundongos
Conformação Proteica
Receptores de Dopamina D1/genética
Receptores de Dopamina D1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, N.I.H., INTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (GTP-Binding Protein alpha Subunits); 0 (Phenanthridines); 0 (Receptors, Dopamine D1); 0 (olfactory G protein subunit alpha olf); 32D64VH037 (dihydrexidine); EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gs)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180207
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02606-w


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[PMID]:28465104
[Au] Autor:Fukuda H; Karaki F; Dodo K; Noguchi-Yachide T; Ishikawa M; Hashimoto Y; Ohgane K
[Ad] Endereço:Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
[Ti] Título:Phenanthridin-6-one derivatives as the first class of non-steroidal pharmacological chaperones for Niemann-Pick disease type C1 protein.
[So] Source:Bioorg Med Chem Lett;27(12):2781-2787, 2017 06 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Niemann-Pick disease type C is a fatal, progressive neurodegenerative disease mostly caused by mutations in Nieamnn-Pick type C1 (NPC1), a late endosomal membrane protein that is essential for intracellular cholesterol transport. The most prevalent mutation, I1061T (Ile to Thr), interferes with the protein folding process. Consequently, mutated but intrinsically functional NPC1 proteins are prematurely degraded via proteasome, leading to loss of NPC1 function. Previously, we reported sterol derivatives as pharmacological chaperones for NPC1, and showed that these derivatives can normalize folding-defective phenotypes of I1061T NPC1 mutant by directly binding to, and stabilizing, the protein. Here, we report a series of compounds containing a phenanthridin-6-one scaffold as the first class of non-steroidal pharmacological chaperones for NPC1. We also examined their structure-activity relationships.
[Mh] Termos MeSH primário: Proteínas de Transporte/antagonistas & inibidores
Glicoproteínas de Membrana/antagonistas & inibidores
Fenantridinas/farmacologia
[Mh] Termos MeSH secundário: Proteínas de Transporte/genética
Proteínas de Transporte/metabolismo
Relação Dose-Resposta a Droga
Seres Humanos
Glicoproteínas de Membrana/genética
Glicoproteínas de Membrana/metabolismo
Estrutura Molecular
Mutação
Fenantridinas/síntese química
Fenantridinas/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Membrane Glycoproteins); 0 (NPC1 protein, human); 0 (Phenanthridines)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171124
[Lr] Data última revisão:
171124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE


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[PMID]:28898076
[Au] Autor:Zhan G; Zhou J; Liu J; Huang J; Zhang H; Liu R; Yao G
[Ad] Endereço:Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430030, People's Republic of China.
[Ti] Título:Acetylcholinesterase Inhibitory Alkaloids from the Whole Plants of Zephyranthes carinata.
[So] Source:J Nat Prod;80(9):2462-2471, 2017 Sep 22.
[Is] ISSN:1520-6025
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Eleven new alkaloids (1-11), classified as the 12-acetylplicamine (1), N-deformyl-seco-plicamine (2), plicamine (3-6), 4a-epi-plicamine (7), seco-plicamine (8), and lycorine (9-11) framework types, along with 15 known alkaloids (12-26) were isolated from the whole plants of Zephyranthes carinata. The structures of the new alkaloids 1-11 were established by extensive spectroscopic data interpretation. The absolute configurations of 9 and 10 were defined by single-crystal X-ray diffraction analysis. Zephycarinatines A (1), B (2), and G (7) represent the first examples of 12-acetylplicamine, N-deformyl-seco-plicamine, and 4a-epi-plicamine alkaloids, respectively. Alkaloids 6, 11, 17, and 20-23 exhibited AChE inhibitory activities with IC values ranging from 1.21 to 184.05 µM, and a preliminary structure-activity relationship is discussed.
[Mh] Termos MeSH primário: Acetilcolinesterase/isolamento & purificação
Acetilcolinesterase/metabolismo
Alcaloides/isolamento & purificação
Alcaloides/farmacologia
Alcaloides de Amaryllidaceae/isolamento & purificação
Alcaloides de Amaryllidaceae/farmacologia
Amaryllidaceae/química
Inibidores da Colinesterase/isolamento & purificação
Inibidores da Colinesterase/farmacologia
Compostos Heterocíclicos de 4 ou mais Anéis/isolamento & purificação
Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia
Liliaceae/química
Fenantridinas/isolamento & purificação
Fenantridinas/farmacologia
[Mh] Termos MeSH secundário: Acetilcolinesterase/química
Alcaloides/química
Alcaloides de Amaryllidaceae/química
Inibidores da Colinesterase/química
Compostos Heterocíclicos de 4 ou mais Anéis/química
Concentração Inibidora 50
Estrutura Molecular
Fenantridinas/química
Relação Estrutura-Atividade
Difração de Raios X
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Alkaloids); 0 (Amaryllidaceae Alkaloids); 0 (Cholinesterase Inhibitors); 0 (Heterocyclic Compounds, 4 or More Rings); 0 (Phenanthridines); 0 (Zephycarinatine G); 0 (plicamine); 0 (zephycarinatine A); 0 (zephycarinatine B); EC 3.1.1.7 (Acetylcholinesterase); I9Q105R5BU (lycorine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170913
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jnatprod.7b00301


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[PMID]:28633894
[Au] Autor:Liu F; Venter H; Bi F; Semple SJ; Liu J; Jin C; Ma S
[Ad] Endereço:Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, PR China.
[Ti] Título:Synthesis and antibacterial activity of 5-methylphenanthridium derivatives as FtsZ inhibitors.
[So] Source:Bioorg Med Chem Lett;27(15):3399-3402, 2017 08 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:5-Methylphenanthridium derivatives were designed, synthesized and evaluated for their in vitro antibacterial activity and cell division inhibitory activity against various Gram-positive and -negative bacteria. Among them, compounds 5A2, 5B1, 5B2, 5B3, 5C1 and 5C2 displayed the best on-target antibacterial activity with an MIC value of 4µg/mL against B. subtilis ATCC9372 and S. pyogenes PS, showing over 2-fold better activity than sanguinarine. The SARs showed that the 5-methylphenanthridium derivatives with the alkyl side chains at the 2-postion, especially the straight alkyl side chains exerted better on-target antibacterial activity.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
Bacillus subtilis/efeitos dos fármacos
Proteínas de Bactérias/antagonistas & inibidores
Proteínas do Citoesqueleto/antagonistas & inibidores
Fenantridinas/farmacologia
Streptococcus pyogenes/efeitos dos fármacos
[Mh] Termos MeSH secundário: Antibacterianos/síntese química
Antibacterianos/química
Relação Dose-Resposta a Droga
Testes de Sensibilidade Microbiana
Estrutura Molecular
Fenantridinas/síntese química
Fenantridinas/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Bacterial Proteins); 0 (Cytoskeletal Proteins); 0 (FtsZ protein, Bacteria); 0 (Phenanthridines)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170622
[St] Status:MEDLINE


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[PMID]:28619258
[Au] Autor:Shimizu Y; Koyama R; Kawamoto T
[Ad] Endereço:Biomolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: yuuji.shimizu@takeda.com.
[Ti] Título:Rho kinase-dependent desensitization of GPR39; a unique mechanism of GPCR downregulation.
[So] Source:Biochem Pharmacol;140:105-114, 2017 Sep 15.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:GPR39, a G-protein-coupled receptor activated by zinc, reportedly activates multiple intracellular signaling pathways via Gs, Gq, G12/13, and ß-arrestin, but little is known about downregulation of the receptor upon its activation. To our knowledge, this is the first report on the mechanism of feedback regulation of GPR39 function determined in GPR39-expressing HEK293 cells (HEK293-GPR39) as a model cell system. In HEK293-GPR39 cells, GPR39-C3, which is a positive allosteric modulator, activated cAMP production (downstream of Gs), IP1 accumulation (downstream of Gq), SRF-RE-dependent transcription (downstream of G12/13), and ß-arrestin recruitment. GPR39-C3 induced dose- and time-dependent loss of response in cAMP production by second challenge of the compound. This functional desensitization was blocked by the Rho kinase (ROCK) inhibitor, Y-27632, but not by Gq or Gs-pathway inhibitors or inhibition of ß-arrestin recruitment. In the receptor localization assay, GPR39-C3 induced internalization of GFP-tagged GPR39. This internalization was also inhibited by Y-27632, which suggested that ROCK activation is critical for internalization and desensitization of GPR39. A novel biased GPR39 positive allosteric modulator, 5-[2-[(2,4-dichlorophenyl)methoxy]phenyl]-2,2-dimethyl-1,3,5,6-tetrahydrobenzo[a]phenanthridin-4-one (GSB-118), which activated cAMP responses and ß-arrestin recruitment but showed no effect on SRF-RE-dependent transcription, did not induce desensitization. These results revealed a unique mechanism of desensitization of GPR39.
[Mh] Termos MeSH primário: AMP Cíclico/metabolismo
Retroalimentação Fisiológica
Receptores Acoplados a Proteínas-G/antagonistas & inibidores
Sistemas do Segundo Mensageiro
Taquifilaxia
Zinco/metabolismo
Quinases Associadas a rho/metabolismo
[Mh] Termos MeSH secundário: Regulação Alostérica/efeitos dos fármacos
Amidas/farmacologia
Retroalimentação Fisiológica/efeitos dos fármacos
Regulação da Expressão Gênica/efeitos dos fármacos
Genes Reporter/efeitos dos fármacos
Proteínas de Fluorescência Verde/genética
Proteínas de Fluorescência Verde/metabolismo
Células HEK293
Seres Humanos
Cinética
Ligantes
Microscopia de Fluorescência
Fenantridinas/farmacologia
Inibidores de Proteínas Quinases/farmacologia
Transporte Proteico/efeitos dos fármacos
Piridinas/farmacologia
Pirimidinas/farmacologia
Receptores Acoplados a Proteínas-G/agonistas
Receptores Acoplados a Proteínas-G/genética
Receptores Acoplados a Proteínas-G/metabolismo
Proteínas Recombinantes de Fusão/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Sistemas do Segundo Mensageiro/efeitos dos fármacos
Sulfonamidas/farmacologia
beta-Arrestinas/metabolismo
Quinases Associadas a rho/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amides); 0 (GPR39 protein, human); 0 (GPR39-C3); 0 (GSB-118); 0 (Ligands); 0 (Phenanthridines); 0 (Protein Kinase Inhibitors); 0 (Pyridines); 0 (Pyrimidines); 0 (Receptors, G-Protein-Coupled); 0 (Recombinant Fusion Proteins); 0 (Recombinant Proteins); 0 (Sulfonamides); 0 (beta-Arrestins); 138381-45-0 (Y 27632); 147336-22-9 (Green Fluorescent Proteins); E0399OZS9N (Cyclic AMP); EC 2.7.11.1 (rho-Associated Kinases); J41CSQ7QDS (Zinc)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170818
[Lr] Data última revisão:
170818
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170617
[St] Status:MEDLINE


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[PMID]:28417947
[Au] Autor:Clere N; To KHT; Legeay S; Bertrand S; Helesbeux JJ; Duval O; Faure S
[Ad] Endereço:MINT, Univ Angers, INSERM, CNRS, Université Bretagne Loire, IBS-CHU, 4 rue Larrey, F-49933 Angers, France. nicolas.clere@univ-angers.fr.
[Ti] Título:Pro-Angiogenic Effects of Low Dose Ethoxidine in a Murine Model of Ischemic Hindlimb: Correlation between Ethoxidine Levels and Increased Activation of the Nitric Oxide Pathway.
[So] Source:Molecules;22(4), 2017 Apr 12.
[Is] ISSN:1420-3049
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Ethoxidine, a benzo[c]phenanthridine derivative, has been identified as a potent inhibitor of topoisomerase I in cancer cell lines. Our group has reported paradoxical properties of ethoxidine in cellular processes leading to angiogenesis on endothelial cells. Because low concentration ethoxidine is able to favor angiogenesis, the present study aimed to investigate the ability of 10 M ethoxidine to modulate neovascularization in a model of mouse hindlimb ischemia. After inducing unilateral hindlimb ischemia, mice were treated for 21 days with glucose 5% or with ethoxidine, to reach plasma concentrations equivalent to 10 M. Laser Doppler analysis showed that recovery of blood flow was 1.5 fold higher in ethoxidine-treated mice in comparison with control mice. Furthermore, CD31 staining and angiographic studies confirmed an increase of vascular density in ethoxidine-treated mice. This ethoxidine-induced recovery was associated with an increase of NO production through an enhancement of eNOS phosphorylation on its activator site in skeletal muscle from ischemic hindlimb. Moreover, real-time RT-PCR and western blots have highlighted that ethoxidine has pro-angiogenic properties by inducing a significant enhancement in vegf transcripts and VEGF expression, respectively. These findings suggest that ethoxidine could contribute to favor neovascularization after an ischemic injury by promoting the NO pathway and VEGF expression.
[Mh] Termos MeSH primário: Indutores da Angiogênese/farmacologia
Membro Posterior/irrigação sanguínea
Membro Posterior/efeitos dos fármacos
Isquemia/metabolismo
Óxido Nítrico/metabolismo
Fenantridinas/farmacologia
[Mh] Termos MeSH secundário: Indutores da Angiogênese/química
Animais
Pressão Sanguínea/efeitos dos fármacos
Peso Corporal/efeitos dos fármacos
Modelos Animais de Doenças
Isquemia/tratamento farmacológico
Masculino
Camundongos
Estrutura Molecular
Músculo Esquelético/efeitos dos fármacos
Músculo Esquelético/metabolismo
Neovascularização Fisiológica/efeitos dos fármacos
Óxido Nítrico Sintase Tipo III/metabolismo
Fenantridinas/química
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 (Angiogenesis Inducing Agents); 0 (Phenanthridines); 0 (Vascular Endothelial Growth Factor A); 0 (ethoxidine); 31C4KY9ESH (Nitric Oxide); EC 1.14.13.39 (Nitric Oxide Synthase Type III)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170531
[Lr] Data última revisão:
170531
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170419
[St] Status:MEDLINE


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[PMID]:28416753
[Au] Autor:Li X; Xu P; Wang C; Xu N; Xu A; Xu Y; Sadahira T; Araki M; Wada K; Matsuura E; Watanabe M; Zheng J; Sun P; Huang P; Nasu Y; Liu C
[Ad] Endereço:Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
[Ti] Título:Synergistic effects of the immune checkpoint inhibitor CTLA-4 combined with the growth inhibitor lycorine in a mouse model of renal cell carcinoma.
[So] Source:Oncotarget;8(13):21177-21186, 2017 Mar 28.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Renal cell carcinoma (RCC) management has undergone a major transformation over the past decade; immune checkpoint inhibitors are currently undergoing clinical trials and show promising results. However, the effectiveness of immune checkpoint inhibitors in patients with metastatic RCC (mRCC) is still limited. Lycorine, an alkaloid extracted from plants of the Amaryllidaceae family, is touted as a potential anti-cancer drug because of its demonstrative growth inhibition capacity (induction of cell cycle arrest and inhibition of vasculogenic mimicry formation). Moreover, T cell checkpoint blockade therapy with antibodies targeting cytotoxic T-lymphocyte associated protein 4 (CTLA-4) has improved outcomes in cancer patients. However, the anti-tumor efficacy of combined lycorine and anti-CTLA-4 therapy remains unknown. Thus, we investigated a combination therapy of lycorine hydrochloride and anti-CTLA-4 using a murine RCC model. As a means of in vitro confirmation, we found that lycorine hydrochloride inhibited the viability of various RCC cell lines. Furthermore, luciferase-expressing Renca cells were implanted in the left kidney and the lung of BALB/c mice to develop a RCC metastatic mouse model. Lycorine hydrochloride and anti-CTLA-4 synergistically decreased tumor weight, lung metastasis, and luciferin-staining in tumor images. Importantly, the observed anti-tumor effects of this combination were dependent on significantly suppressing regulatory T cells while upregulating effector T cells; a decrease in regulatory T cells by 31.43% but an increase in effector T cells by 31.59% were observed in the combination group compared with those in the control group). We suggest that a combination of lycorine hydrochloride and anti-CTLA-4 is a viable therapeutic option for RCC patients.
[Mh] Termos MeSH primário: Alcaloides de Amaryllidaceae/farmacologia
Anticorpos Monoclonais/farmacologia
Antineoplásicos/farmacologia
Antígeno CTLA-4/antagonistas & inibidores
Carcinoma de Células Renais/terapia
Inibidores do Crescimento/farmacologia
Fenantridinas/farmacologia
Extratos Vegetais/farmacologia
[Mh] Termos MeSH secundário: Alcaloides de Amaryllidaceae/uso terapêutico
Animais
Anticorpos Monoclonais/uso terapêutico
Antineoplásicos/uso terapêutico
Carcinoma de Células Renais/tratamento farmacológico
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Terapia Combinada
Sinergismo Farmacológico
Feminino
Inibidores do Crescimento/uso terapêutico
Seres Humanos
Fatores Imunológicos/farmacologia
Fatores Imunológicos/uso terapêutico
Imunoterapia/métodos
Camundongos
Camundongos Endogâmicos BALB C
Neoplasias Experimentais
Fenantridinas/uso terapêutico
Extratos Vegetais/uso terapêutico
Subpopulações de Linfócitos T/efeitos dos fármacos
Subpopulações de Linfócitos T/imunologia
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amaryllidaceae Alkaloids); 0 (Antibodies, Monoclonal); 0 (Antineoplastic Agents); 0 (CTLA-4 Antigen); 0 (Ctla4 protein, mouse); 0 (Growth Inhibitors); 0 (Immunologic Factors); 0 (Phenanthridines); 0 (Plant Extracts); I9Q105R5BU (lycorine)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170524
[Lr] Data última revisão:
170524
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170419
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15505


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[PMID]:28351327
[Au] Autor:Yakisich JS; Azad N; Kaushik V; O'Doherty GA; Iyer AK
[Ad] Endereço:1 Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, VA, USA.
[Ti] Título:Nigericin decreases the viability of multidrug-resistant cancer cells and lung tumorspheres and potentiates the effects of cardiac glycosides.
[So] Source:Tumour Biol;39(3):1010428317694310, 2017 Mar.
[Is] ISSN:1423-0380
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Multiple factors including tumor heterogeneity and intrinsic or acquired resistance have been associated with drug resistance in lung cancer. Increased stemness and the plasticity of cancer cells have been identified as important mechanisms of resistance; therefore, treatments targeting cancer cells independent of stemness phenotype would be much more effective in treating lung cancer. In this article, we have characterized the anticancer effects of the antibiotic Nigericin in cells displaying varying degrees of stemness and resistance to anticancer drugs, arising from (1) routine culture conditions, (2) prolonged periods of serum starvation. These cells are highly resistant to conventional anticancer drugs such as Paclitaxel, Hydroxyurea, Colchicine, Obatoclax, Wortmannin, and LY294002, and the multidrug-resistant phenotype of cells growing under prolonged periods of serum starvation is likely the result of extensive rewiring of signaling pathways, and (3) lung tumorspheres that are enriched for cancer stem-like cells. We found that Nigericin potently inhibited the viability of cells growing under routine culture conditions, prolonged periods of serum starvation, and lung tumorspheres. In addition, we found that Nigericin downregulated the expression of key proteins in the Wnt canonical signaling pathway such as LRP6, Wnt5a/b, and ß-catenin, but promotes ß-catenin translocation into the nucleus. The antitumor effects of Nigericin were potentiated by the Wnt activator HLY78 and by therapeutic levels of the US Food and Drug Administration-approved drug Digitoxin and its novel synthetic analog MonoD. We believe that Nigericin may be used in a co-therapy model in combination with other novel chemotherapeutic agents in order to achieve potent inhibition of cancers that display varying degrees of stemness, potentially leading to sustained anticancer effects.
[Mh] Termos MeSH primário: Benzodioxóis/administração & dosagem
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Neoplasias Pulmonares/tratamento farmacológico
Nigericina/administração & dosagem
Fenantridinas/administração & dosagem
[Mh] Termos MeSH secundário: Antineoplásicos/administração & dosagem
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Resistência a Múltiplos Medicamentos/efeitos dos fármacos
Seres Humanos
Neoplasias Pulmonares/genética
Neoplasias Pulmonares/patologia
Células-Tronco Neoplásicas/efeitos dos fármacos
Via de Sinalização Wnt/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (4-ethyl-5-methyl-5,6-dihydro(1,3)dioxolo(4,5-j)phenanthridine); 0 (Antineoplastic Agents); 0 (Benzodioxoles); 0 (Phenanthridines); RRU6GY95IS (Nigericin)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170407
[Lr] Data última revisão:
170407
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170330
[St] Status:MEDLINE
[do] DOI:10.1177/1010428317694310


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[PMID]:28288771
[Au] Autor:Tchamdja E; Kulo AE; Vitouley HS; Batawui K; Bankolé AA; Adomefa K; Cecchi G; Hoppenheit A; Clausen PH; De Deken R; Van Den Abbeele J; Marcotty T; Delespaux V
[Ad] Endereço:Direction de l'Elevage, BP 4041, Lomé, Togo.
[Ti] Título:Cattle breeding, trypanosomosis prevalence and drug resistance in Northern Togo.
[So] Source:Vet Parasitol;236:86-92, 2017 Mar 15.
[Is] ISSN:1873-2550
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:African Animal Trypanosomosis (AAT) is a major disease of cattle in Togo and its control is essentially based on chemotherapy. However, because of excessive use of trypanocides during the past decades, chemo-resistance in the parasites has developed. In order to assess the current situation of AAT and resistance to trypanocidal drugs in Northern Togo, a study was conducted on cattle from December 2012 to August 2013 in the regions of Kara and Savanes. An initial cross-sectional survey was carried out in 40 villages using the Haematocrit Centrifugation Technique (HCT). Out of these, 5 villages with a trypanosome prevalence of >10% were selected for a block treatment study (BT) with diminazene diaceturate (DA: 3.5mg/kg for a 14-day follow-up) and isometamidium chloride (ISM: 0.5mg/kg for a 28-day follow-up). Positive blood samples collected during the parasitological surveys and an equivalent number of negatives were further analyzed by PCR-RFLP for trypanosome species confirmation and molecular diagnosis of resistance to DA in Trypanosoma congolense. The results from 1883 bovine blood samples confirmed a high overall trypanosome prevalence of 10.8% in Northern Togo. PCR-RFLP revealed that T. congolense is the dominant pathogenic trypanosome species (50.5%) followed by T. vivax (27.3%), and T. brucei (16.2%). The BT showed varying levels of treatment failures ranging from 0 to 30% and from 0 to 50% for DA and for ISM respectively, suggesting the existence of resistant trypanosome populations in the study area. Our results show that AAT still represents a major obstacle to the development of cattle husbandry in Northern Togo. In areas of high AAT risk, a community-based integrated strategy combining vector control, rational use of trypanocidal drugs and improving the general condition of the animals is recommended to decision makers.
[Mh] Termos MeSH primário: Doenças dos Bovinos/prevenção & controle
Resistência a Medicamentos
Tripanossomicidas/farmacologia
Trypanosoma congolense/efeitos dos fármacos
Tripanossomíase Africana/veterinária
Tripanossomíase Bovina/parasitologia
[Mh] Termos MeSH secundário: Animais
Cruzamento
Bovinos
Doenças dos Bovinos/epidemiologia
Doenças dos Bovinos/parasitologia
Controle de Doenças Transmissíveis
Estudos Transversais
Diminazena/análogos & derivados
Diminazena/farmacologia
Fenantridinas/farmacologia
Prevalência
Togo/epidemiologia
Falha de Tratamento
Trypanosoma/efeitos dos fármacos
Tripanossomíase/epidemiologia
Tripanossomíase/parasitologia
Tripanossomíase/prevenção & controle
Tripanossomíase/veterinária
Tripanossomíase Africana/epidemiologia
Tripanossomíase Africana/parasitologia
Tripanossomíase Africana/prevenção & controle
Tripanossomíase Bovina/epidemiologia
Tripanossomíase Bovina/prevenção & controle
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Phenanthridines); 0 (Trypanocidal Agents); 7NH28I651F (isometamidium chloride); JI8SAD85NO (diminazene aceturate); Y5G36EEA5Z (Diminazene)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170908
[Lr] Data última revisão:
170908
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170315
[St] Status:MEDLINE


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[PMID]:28263311
[Au] Autor:Bruno PM; Liu Y; Park GY; Murai J; Koch CE; Eisen TJ; Pritchard JR; Pommier Y; Lippard SJ; Hemann MT
[Ad] Endereço:The Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA.
[Ti] Título:A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress.
[So] Source:Nat Med;23(4):461-471, 2017 Apr.
[Is] ISSN:1546-170X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cisplatin and its platinum analogs, carboplatin and oxaliplatin, are some of the most widely used cancer chemotherapeutics. Although cisplatin and carboplatin are used primarily in germ cell, breast and lung malignancies, oxaliplatin is instead used almost exclusively to treat colorectal and other gastrointestinal cancers. Here we utilize a unique, multi-platform genetic approach to study the mechanism of action of these clinically established platinum anti-cancer agents, as well as more recently developed cisplatin analogs. We show that oxaliplatin, unlike cisplatin and carboplatin, does not kill cells through the DNA-damage response. Rather, oxaliplatin kills cells by inducing ribosome biogenesis stress. This difference in drug mechanism explains the distinct clinical implementation of oxaliplatin relative to cisplatin, and it might enable mechanistically informed selection of distinct platinum drugs for distinct malignancies. These data highlight the functional diversity of core components of front-line cancer therapy and the potential benefits of applying a mechanism-based rationale to the use of our current arsenal of anti-cancer drugs.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Carboplatina/farmacologia
Cisplatino/farmacologia
Neoplasias
Biogênese de Organelas
Compostos Organoplatínicos/farmacologia
Ribossomos/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Western Blotting
Linhagem Celular Tumoral
Dano ao DNA/efeitos dos fármacos
Seres Humanos
Camundongos
Fenantridinas/farmacologia
Compostos de Platina/farmacologia
Análise de Componente Principal
RNA Interferente Pequeno
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Estresse Fisiológico
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Organoplatinum Compounds); 0 (Phenanthridines); 0 (Platinum Compounds); 0 (RNA, Small Interfering); 0 (phenanthriplatin); 04ZR38536J (oxaliplatin); BG3F62OND5 (Carboplatin); Q20Q21Q62J (Cisplatin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170307
[St] Status:MEDLINE
[do] DOI:10.1038/nm.4291



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