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[PMID]:29268130
[Au] Autor:Lin HY; Han HW; Sun WX; Yang YS; Tang CY; Lu GH; Qi JL; Wang XM; Yang YH
[Ad] Endereço:State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing, 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing, 210037, China.
[Ti] Título:Design and characterization of α-lipoic acyl shikonin ester twin drugs as tubulin and PDK1 dual inhibitors.
[So] Source:Eur J Med Chem;144:137-150, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Shikonin exhibits powerful anticancer activities for various cancer cells, but its poor solubility and strong toxicity hinder its development as clinical anticancer agent. We previously confirmed that shikonin and its derivatives can disturb mitosis through targeting tubulin. In this study, α-lipoic acid, the naturally-occurring co-factor of pyruvate dehydrogenase (PDH), was introduced into shikonin to design the twin drugs against both mitosis (tubulin) and glycolysis (PDK). 18 kinds of α-lipoic acid shikonin ester derivatives were achieved through three rounds of screening process performed by computer assistant drug design method, being designated as the outstanding compounds. Among them, 1c displayed the most potent cytotoxicity towards cervical cancer cells (HeLa) with an IC value of 3.14 ± 0.58 µM and inhibited xenotransplanted tumor growth in a dose-dependent manner. Further pharmacologic study demonstrated that 1c can cause cell cycle arrest in G2/M phase as tubulin polymerization inhibitor. Moreover, it also showed good PDK1 inhibitory activity, promoting PDH activity and forced HeLa cells to process more aerobic metabolism to undergo cell apoptosis. We reported here the first dual inhibitors of tubulin and PDK1 based on shikonin. It may form a basis for shikonin optimization through twin drug design framework for the discovery of new and potent shikonin derivatives in the study of targeted cancer therapy.
[Mh] Termos MeSH primário: Antineoplásicos/química
Antineoplásicos/farmacologia
Naftoquinonas/química
Naftoquinonas/farmacologia
Proteínas Serina-Treonina Quinases/antagonistas & inibidores
Moduladores de Tubulina/química
Moduladores de Tubulina/farmacologia
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Desenho de Drogas
Glicólise/efeitos dos fármacos
Células HeLa
Seres Humanos
Mitose/efeitos dos fármacos
Neoplasias/tratamento farmacológico
Neoplasias/metabolismo
Proteínas Serina-Treonina Quinases/metabolismo
Tubulina (Proteína)/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Naphthoquinones); 0 (Tubulin); 0 (Tubulin Modulators); 3IK6592UBW (shikonin); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.2 (pyruvate dehydrogenase (acetyl-transferring) kinase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171222
[St] Status:MEDLINE


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[PMID]:29289882
[Au] Autor:Lara LS; Moreira CS; Calvet CM; Lechuga GC; Souza RS; Bourguignon SC; Ferreira VF; Rocha D; Pereira MCS
[Ad] Endereço:Laboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365 Manguinhos, 21040-900 Rio de Janeiro, RJ, Brazil.
[Ti] Título:Efficacy of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinone derivatives against different Trypanosoma cruzi discrete type units: Identification of a promising hit compound.
[So] Source:Eur J Med Chem;144:572-581, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:The limited efficacy of benznidazole (Bz) indicated by failures of current Phase II clinical trials emphasizes the urgent need to identify new drugs with improved safety and efficacy for treatment of Chagas disease (CD). Herein, we analyzed the efficacy of a series of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones against different Trypanosoma cruzi discrete type units (DTUs) of relevant clinical forms of CD. Cytotoxic and trypanocidal effect of naphthoquinone derivatives were assessed in mammalian cells, trypomastigotes and intracellular amastigotes using, luminescent assays (CellTiter-Glo and T. cruzi Dm28c-luciferase) and/or counting with a light microscope. Reactive oxygen species (ROS) production and intracellular targets of promising compounds were assessed with 2',7'-dichlorodihydrofluorescein diacetate (H DCFDA) probe and ultrastructural analysis, respectively. ADMET properties were analyzed by in silico modeling. Most of the compounds showed low cytotoxic effect. Only two compounds (Compounds 2 and 11) had IC values lower than Bz, showing higher susceptibility of bloodstream trypomastigotes. Compound 2 exhibited greater efficacy against trypomastigotes from different T. cruzi DTUs, even better than Bz against Brazil and CL strains. Ultrastructural analysis revealed changes in intracellular compartments, suggesting autophagy as one possible mechanism of action. Oxidative stress, induced by Compound 2, resulted in elevated level of ROS, leading to parasite death. Compound 2 was also effective against intracellular amastigotes, showing high selectivity index. ADMET analysis predicted good oral bioavailability, reduced drug metabolism and no carcinogenic potential for Compound 2. The data highlight Compound 2 as a hit compound and stimulate further structural and pharmacological optimization to potentiate its trypanocidal activity and selectivity.
[Mh] Termos MeSH primário: Naftoquinonas/farmacologia
Tripanossomicidas/farmacologia
Trypanosoma cruzi/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Cercopithecus aethiops
Relação Dose-Resposta a Droga
Macaca mulatta
Estrutura Molecular
Naftoquinonas/síntese química
Naftoquinonas/química
Testes de Sensibilidade Parasitária
Espécies Reativas de Oxigênio/metabolismo
Relação Estrutura-Atividade
Tripanossomicidas/síntese química
Tripanossomicidas/química
Trypanosoma cruzi/metabolismo
Células Vero
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Naphthoquinones); 0 (Reactive Oxygen Species); 0 (Trypanocidal Agents)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180101
[St] Status:MEDLINE


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[PMID]:29324340
[Au] Autor:Brandão GC; Rocha Missias FC; Arantes LM; Soares LF; Roy KK; Doerksen RJ; Braga de Oliveira A; Pereira GR
[Ad] Endereço:Departamento de Farmácia, Escola de Farmácia, UFOP, Campus Morro do Cruzeiro, s/n, Balxita, CEP 35400-000, Ouro Preto, MG, Brazil.
[Ti] Título:Antimalarial naphthoquinones. Synthesis via click chemistry, in vitro activity, docking to PfDHODH and SAR of lapachol-based compounds.
[So] Source:Eur J Med Chem;145:191-205, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Lapachol is an abundant prenyl naphthoquinone occurring in Brazilian Bignoniaceae that was clinically used, in former times, as an antimalarial drug, despite its moderate effect. Aiming to search for potentially better antimalarials, a series of 1,2,3-triazole derivatives was synthesized by chemical modification of lapachol. Alkylation of the hydroxyl group gave its propargyl ether which, via copper-catalyzed cycloaddition (CuAAC) click chemistry with different organic azides, afforded 17 naphthoquinonolyl triazole derivatives. All the synthetic compounds were evaluated for their in vitro activity against chloroquine resistant Plasmodium falciparum (W2) and for cytotoxicity to HepG2 cells. Compounds containing the naphthoquinolyl triazole moieties showed higher antimalarial activity than lapachol (IC 123.5 µM) and selectivity index (SI) values in the range of 4.5-197.7. Molecular docking simulations of lapachol, atovaquone and all the newly synthesized compounds were carried out for interactions with PfDHODH, a mitochondrial enzyme of the parasite respiratory chain that is essential for de novo pyrimidine biosynthesis. Docking of the naphthoquinonolyl triazole derivatives to PfDHODH yielded scores between -9.375 and -14.55 units, compared to -9.137 for lapachol and -12.95 for atovaquone and disclosed the derivative 17 as a lead compound. Therefore, the study results show the enhancement of DHODH binding affinity correlated with improvement of SI values and in vitro activities of the lapachol derivatives.
[Mh] Termos MeSH primário: Antimaláricos/farmacologia
Naftoquinonas/farmacologia
Plasmodium falciparum/efeitos dos fármacos
[Mh] Termos MeSH secundário: Antimaláricos/síntese química
Antimaláricos/química
Sobrevivência Celular/efeitos dos fármacos
Cloroquina/farmacologia
Química Click
Relação Dose-Resposta a Droga
Resistência a Medicamentos/efeitos dos fármacos
Células Hep G2
Seres Humanos
Modelos Moleculares
Estrutura Molecular
Naftoquinonas/química
Testes de Sensibilidade Parasitária
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antimalarials); 0 (Naphthoquinones); 886U3H6UFF (Chloroquine); B221938VB6 (lapachol)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180112
[St] Status:MEDLINE


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[PMID]:29298345
[Au] Autor:Siegel D; Dehn DD; Bokatzian SS; Quinn K; Backos DS; Di Francesco A; Bernier M; Reisdorph N; de Cabo R; Ross D
[Ad] Endereço:Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
[Ti] Título:Redox modulation of NQO1.
[So] Source:PLoS One;13(1):e0190717, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:NQO1 is a FAD containing NAD(P)H-dependent oxidoreductase that catalyzes the reduction of quinones and related substrates. In cells, NQO1 participates in a number of binding interactions with other proteins and mRNA and these interactions may be influenced by the concentrations of reduced pyridine nucleotides. NAD(P)H can protect NQO1 from proteolytic digestion suggesting that binding of reduced pyridine nucleotides results in a change in NQO1 structure. We have used purified NQO1 to demonstrate the addition of NAD(P)H induces a change in the structure of NQO1; this results in the loss of immunoreactivity to antibodies that bind to the C-terminal domain and to helix 7 of the catalytic core domain. Under normal cellular conditions NQO1 is not immunoprecipitated by these antibodies, however, following treatment with ß-lapachone which caused rapid oxidation of NAD(P)H NQO1 could be readily pulled-down. Similarly, immunostaining for NQO1 was significantly increased in cells following treatment with ß-lapachone demonstrating that under non-denaturing conditions the immunoreactivity of NQO1 is reflective of the NAD(P)+/NAD(P)H ratio. In untreated human cells, regions with high intensity immunostaining for NQO1 co-localize with acetyl α-tubulin and the NAD+-dependent deacetylase Sirt2 on the centrosome(s), the mitotic spindle and midbody during cell division. These data provide evidence that during the centriole duplication cycle NQO1 may provide NAD+ for Sirt2-mediated deacetylation of microtubules. Overall, NQO1 may act as a redox-dependent switch where the protein responds to the NAD(P)+/NAD(P)H redox environment by altering its structure promoting the binding or dissociation of NQO1 with target macromolecules.
[Mh] Termos MeSH primário: NAD(P)H Desidrogenase (Quinona)/metabolismo
[Mh] Termos MeSH secundário: Domínio Catalítico
Linhagem Celular
Eletroforese em Gel de Poliacrilamida
Técnicas de Silenciamento de Genes
Seres Humanos
Imunoprecipitação
Espectrometria de Massas
NAD(P)H Desidrogenase (Quinona)/genética
Naftoquinonas/farmacologia
Eletroforese em Gel de Poliacrilamida Nativa
Oxirredução
RNA Interferente Pequeno/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Naphthoquinones); 0 (RNA, Small Interfering); 4707-32-8 (beta-lapachone); EC 1.6.5.2 (NAD(P)H Dehydrogenase (Quinone)); EC 1.6.5.2 (NQO1 protein, human)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180104
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190717


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[PMID]:29292470
[Au] Autor:Kehelpannala C; Kumar NS; Jayasinghe L; Araya H; Fujimoto Y
[Ad] Endereço:National Institute of Fundamental Studies, Hantana Road, Kandy, Sri Lanka.
[Ti] Título:Naphthoquinone Metabolites Produced by Monacrosporium ambrosium, the Ectosymbiotic Fungus of Tea Shot-Hole Borer, Euwallacea fornicatus, in Stems of Tea, Camellia sinensis.
[So] Source:J Chem Ecol;44(1):95-101, 2018 Jan.
[Is] ISSN:1573-1561
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The tea shot-hole borer beetle (TSHB, Euwallacea fornicatus) causes serious damage in plantations of tea, Camellia sinensis var. assamica, in Sri Lanka and South India. TSHB is found in symbiotic association with the ambrosia fungus, Monacrosporium ambrosium (syn. Fusarium ambrosium), in galleries located within stems of tea bushes. M. ambrosium is known to be the sole food source of TSHB. Six naphthoquinones produced during spore germination in a laboratory culture broth of M. ambrosium were isolated and identified as dihydroanhydrojavanicin, anhydrojavanicin, javanicin, 5,8-dihydroxy-2-methyl-3-(2-oxopropyl)naphthalene-1,4-dione, anhydrofusarubin and solaniol. Chloroform extracts of tea stems with red-colored galleries occupied by TSHB contained UV active compounds similar to the above naphthoquinones. Laboratory assays demonstrated that the combined ethyl acetate extracts of the fungal culture broth and mycelium inhibited the growth of endophytic fungi Pestalotiopsis camelliae and Phoma multirostrata, which were also isolated from tea stems. Thus, pigmented naphthoquinones secreted by M. ambrosium during spore germination may prevent other fungi from invading TSHB galleries in tea stems. The antifungal nature of the naphthoquinone extract suggests that it protects the habitat of TSHB. We propose that the TSHB fungal ectosymbiont M. ambrosium provides not only the food and sterol skeleton necessary for the development of the beetle during its larval stages, but also serves as a producer of fungal inhibitors that help to preserve the purity of the fungal garden of TSHB.
[Mh] Termos MeSH primário: Ascomicetos/química
Camellia sinensis/microbiologia
Coleópteros/microbiologia
Naftoquinonas/análise
[Mh] Termos MeSH secundário: Animais
Antifúngicos/química
Antifúngicos/isolamento & purificação
Antifúngicos/farmacologia
Ascomicetos/efeitos dos fármacos
Ascomicetos/fisiologia
Camellia sinensis/crescimento & desenvolvimento
Clorofórmio/química
Ecossistema
Espectroscopia de Ressonância Magnética
Naftoquinonas/isolamento & purificação
Naftoquinonas/farmacologia
Caules de Planta/química
Caules de Planta/microbiologia
Esporos Fúngicos/química
Esporos Fúngicos/crescimento & desenvolvimento
Simbiose
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antifungal Agents); 0 (Naphthoquinones); 7V31YC746X (Chloroform)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180103
[St] Status:MEDLINE
[do] DOI:10.1007/s10886-017-0913-1


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[PMID]:29248571
[Au] Autor:Jarolim K; Wolters K; Woelflingseder L; Pahlke G; Beisl J; Puntscher H; Braun D; Sulyok M; Warth B; Marko D
[Ad] Endereço:University of Vienna, Faculty of Chemistry, Department of Food Chemistry and Toxicology, Währinger Straße 38, 1090 Vienna, Austria.
[Ti] Título:The secondary Fusarium metabolite aurofusarin induces oxidative stress, cytotoxicity and genotoxicity in human colon cells.
[So] Source:Toxicol Lett;284:170-183, 2018 Mar 01.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Aurofusarin (AURO), a dimeric naphthoquinone, is produced by Fusarium fungi. Although frequently found in food and feed, toxicological studies are limited. Hence, the in vitro toxicity of AURO was investigated in the colon adenocarcinoma cell line HT29 and the non-tumorigenic colon cells HCEC-1CT. Cytotoxic effects were found at concentrations ≥1 µM by evaluating mitochondrial activity (WST-1) and cellular proliferation (sulforhodamine B assay). 10 µM of AURO induced a decrease of cells in the S-phase, measured by flow cytometry. Confocal microscopy revealed AURO-mediated increase of intracellular p53 protein. In accordance, DNA-damage was seen in the comet assay (≥1 µM) together with enhanced levels of formamidopyrimidine-DNA-glycosylase (fpg)-sensitive sites, indicative for oxidative stress. An increase of intracellular reactive oxygen species was observed in the dichlorofluorescein (DCF) assay (≥5 µM). The GSSG/GSH ratio was elevated, but no impact on redox-sensitive Nrf2-dependent genes (Nrf2, γ-GCL, NQO1) was found at the gene expression level. However, induction of cytochrome P450 monooxygenase (CYP) 1A1 was measured at the gene expression and protein level. In conclusion, these in vitro data suggest that, when co-occurring, AURO might be considered as a potential contributor to the overall toxicity of respective Fusarium mycotoxin mixtures.
[Mh] Termos MeSH primário: Colo/efeitos dos fármacos
Dano ao DNA
Fusarium/metabolismo
Mutagênicos/toxicidade
Naftoquinonas/toxicidade
Estresse Oxidativo/efeitos dos fármacos
[Mh] Termos MeSH secundário: Técnicas de Cultura de Células
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Colo/metabolismo
Colo/patologia
Ensaio Cometa
Citometria de Fluxo
Células HT29
Seres Humanos
Mutagênicos/isolamento & purificação
Naftoquinonas/isolamento & purificação
Fase S/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Mutagens); 0 (Naphthoquinones); EYG3R23SI1 (aurofusarin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171218
[St] Status:MEDLINE


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[PMID]:28465296
[Au] Autor:Nyquist MD; Corella A; Burns J; Coleman I; Gao S; Tharakan R; Riggan L; Cai C; Corey E; Nelson PS; Mostaghel EA
[Ad] Endereço:Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.
[Ti] Título:Exploiting AR-Regulated Drug Transport to Induce Sensitivity to the Survivin Inhibitor YM155.
[So] Source:Mol Cancer Res;15(5):521-531, 2017 05.
[Is] ISSN:1557-3125
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Androgen receptor (AR) signaling is fundamental to prostate cancer and is the dominant therapeutic target in metastatic disease. However, stringent androgen deprivation therapy regimens decrease quality of life and have been largely unsuccessful in curtailing mortality. Recent clinical and preclinical studies have taken advantage of the dichotomous ability of AR signaling to elicit growth-suppressive and differentiating effects by administering hyperphysiologic levels of testosterone. In this study, high-throughput drug screening identified a potent synergy between high-androgen therapy and YM155, a transcriptional inhibitor of survivin (BIRC5). This interaction was mediated by the direct transcriptional upregulation of the YM155 transporter SLC35F2 by the AR. Androgen-mediated YM155-induced cell death was completely blocked by the overexpression of multidrug resistance transporter ABCB1. SLC35F2 expression was significantly correlated with intratumor androgen levels in four distinct patient-derived xenograft models, and with AR activity score in a large gene expression dataset of castration-resistant metastases. A subset of tumors had significantly elevated SLC35F2 expression and, therefore, may identify patients who are highly responsive to YM155 treatment. IMPLICATIONS: The combination of androgen therapy with YM155 represents a novel drug synergy, and SLC35F2 may serve as a clinical biomarker of response to YM155.
[Mh] Termos MeSH primário: Androgênios/administração & dosagem
Imidazóis/administração & dosagem
Proteínas de Membrana Transportadoras/genética
Naftoquinonas/administração & dosagem
Neoplasias da Próstata/tratamento farmacológico
Receptores Androgênicos/metabolismo
[Mh] Termos MeSH secundário: Androgênios/farmacologia
Animais
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Sinergismo Farmacológico
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Imidazóis/farmacologia
Masculino
Camundongos
Naftoquinonas/farmacologia
Neoplasias da Próstata/genética
Neoplasias da Próstata/metabolismo
Transdução de Sinais/efeitos dos fármacos
Testosterona/administração & dosagem
Testosterona/farmacologia
Resultado do Tratamento
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AR protein, human); 0 (Androgens); 0 (Imidazoles); 0 (Membrane Transport Proteins); 0 (Naphthoquinones); 0 (Receptors, Androgen); 0 (SLC35F2 protein, human); 0 (YM 155); 3XMK78S47O (Testosterone)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1158/1541-7786.MCR-16-0315-T


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[PMID]:29225125
[Au] Autor:Shimada N; Takasawa R; Tanuma SI
[Ad] Endereço:Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
[Ti] Título:Interdependence of GLO I and PKM2 in the Metabolic shift to escape apoptosis in GLO I-dependent cancer cells.
[So] Source:Arch Biochem Biophys;638:1-7, 2018 01 15.
[Is] ISSN:1096-0384
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Many cancer cells undergo metabolic reprogramming known as the Warburg effect, which is characterized by a greater dependence on glycolysis for ATP generation, even under normoxic conditions. Glyoxalase I (GLO I) is a rate-limiting enzyme involved in the detoxification of cytotoxic methylglyoxal formed in glycolysis and which is known to be highly expressed in many cancer cells. Thus, specific inhibitors of GLO I are expected to be effective anticancer drugs. We previously discovered a novel GLO I inhibitor named TLSC702. Although the strong inhibitory activity of TLSC702 was observed in the in vitro enzyme assay, higher concentrations were required to induce apoptosis at the cellular level. One of the proposed reasons for this difference is that cancer cells alter the energy metabolism leading them to become more dependent on mitochondrial respiration than glycolysis (Metabolic shift) to avoid apoptosis induction. Thus, we assumed that combination of TLSC702 with shikonin-a specific inhibitor of pyruvate kinase M2 (PKM2) that acts as a driver of TCA cycle by supplying pyruvate and which is known to be specifically expressed in cancer cells-would have anticancer effects. We herein show the anticancer effects of combination treatment with TLSC702 and shikonin, and a possible anticancer mechanism.
[Mh] Termos MeSH primário: Apoptose
Proteínas de Transporte/metabolismo
Lactoilglutationa Liase/metabolismo
Proteínas de Membrana/metabolismo
Proteínas de Neoplasias/metabolismo
Neoplasias/enzimologia
Piruvato Quinase/metabolismo
Hormônios Tireóideos/metabolismo
[Mh] Termos MeSH secundário: Butiratos/farmacologia
Proteínas de Transporte/antagonistas & inibidores
Proteínas de Transporte/genética
Linhagem Celular Tumoral
Ciclo do Ácido Cítrico/efeitos dos fármacos
Ensaios de Seleção de Medicamentos Antitumorais
Seres Humanos
Lactoilglutationa Liase/antagonistas & inibidores
Lactoilglutationa Liase/genética
Proteínas de Membrana/antagonistas & inibidores
Proteínas de Membrana/genética
Naftoquinonas/farmacologia
Proteínas de Neoplasias/antagonistas & inibidores
Proteínas de Neoplasias/genética
Neoplasias/tratamento farmacológico
Neoplasias/genética
Neoplasias/patologia
Piruvato Quinase/antagonistas & inibidores
Piruvato Quinase/genética
Ácido Pirúvico/metabolismo
Tiazóis/farmacologia
Hormônios Tireóideos/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (3-(1,3-benzothiazol-2-yl)-4-(4-methoxyphenyl)but-3-enoic acid); 0 (Butyrates); 0 (Carrier Proteins); 0 (Membrane Proteins); 0 (Naphthoquinones); 0 (Neoplasm Proteins); 0 (Thiazoles); 0 (Thyroid Hormones); 0 (thyroid hormone-binding proteins); 3IK6592UBW (shikonin); 8558G7RUTR (Pyruvic Acid); EC 2.7.1.40 (Pyruvate Kinase); EC 4.4.1.5 (GLO1 protein, human); EC 4.4.1.5 (Lactoylglutathione Lyase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171212
[St] Status:MEDLINE


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[PMID]:27770268
[Au] Autor:Sajadimajd S; Yazdanparast R
[Ad] Endereço:Institute of Biochemistry and Biophysics, University of Tehran, P. O. Box 13145-1384, Tehran, Iran.
[Ti] Título:Sensitizing effect of juglone is mediated by down regulation of Notch1 signaling pathway in trastuzumab-resistant SKBR3 cells.
[So] Source:Apoptosis;22(1):135-144, 2017 Jan.
[Is] ISSN:1573-675X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Trastuzumab (Herceptin) monoclonal antibody directed against HER2 receptor has been administered as a treatment for metastatic HER2 positive breast cancer. The problematic issue in treatment of HER2 positive breast cancer cells is commonly the induction of resistance to trastuzumab which might be due to modulation of some vital signaling elements such as Notch1 and Pin1. In this study, we were aimed to investigate whether the cross talk between pin1 and Notch1 has a role in this event. Our results indicated that the expression level of Pin1 in resistant SKBR3 cells increased by about twofold relative to sensitive SKBR3 cells. Besides, Pin1 inhibition via juglone reduced the extent of proliferation, colony formation and migration capacity of resistant SKBR3 cells. In addition, despite a feed forward loop between Notch1 and Pin1 in sensitive SKBR3 cells, inhibition of Notch1 cleavage in resistant SKBR3 cells did not affect pin1 level whereas pin1 inhibition by juglone reduced the level of Hes1, p-Akt and increased the cellular content of Numb. Therefore, we concluded that pin1 inhibition could be considered as a promising sensitizing strategy to weaken trastuzumab resistance.
[Mh] Termos MeSH primário: Neoplasias da Mama/tratamento farmacológico
Peptidilprolil Isomerase de Interação com NIMA/genética
Naftoquinonas/administração & dosagem
Receptor Notch1/genética
[Mh] Termos MeSH secundário: Neoplasias da Mama/genética
Neoplasias da Mama/patologia
Resistência a Medicamentos Antineoplásicos/genética
Feminino
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Proteínas de Membrana/genética
Proteínas do Tecido Nervoso/genética
Proteínas Proto-Oncogênicas c-akt/genética
Receptor ErbB-2/genética
Transdução de Sinais/efeitos dos fármacos
Fatores de Transcrição HES-1/genética
Trastuzumab/administração & dosagem
Trastuzumab/efeitos adversos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Membrane Proteins); 0 (NIMA-Interacting Peptidylprolyl Isomerase); 0 (Naphthoquinones); 0 (Nerve Tissue Proteins); 0 (Numb protein, human); 0 (Receptor, Notch1); 0 (Transcription Factor HES-1); 149348-15-2 (HES1 protein, human); EC 2.7.10.1 (ERBB2 protein, human); EC 2.7.10.1 (Receptor, ErbB-2); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 5.2.1.8 (PIN1 protein, human); P188ANX8CK (Trastuzumab); W6Q80SK9L6 (juglone)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180212
[Lr] Data última revisão:
180212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161023
[St] Status:MEDLINE
[do] DOI:10.1007/s10495-016-1291-9


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[PMID]:29235324
[Au] Autor:Bezkorovaynyj AO; Zyn AR; Harasym NM; Len JT; Figurka OM; Sanagursky DI
[Ti] Título:Loach embryos prooxidant-antioxidant status under the influence of amide derivatives of 1,4-naphthoquinone.
[So] Source:Ukr Biochem J;88(3):46-53, 2016 May-Jun.
[Is] ISSN:2409-4943
[Cp] País de publicação:Ukraine
[La] Idioma:eng
[Ab] Resumo:The mechanisms of disorders in cell functions induced by 1,4-naphthoquinone amide derivatives are not clarified yet. The article is dedicated to the study of features of these substances influence on loach Misgurnus fossilis L. embryos pro/antioxidant homeostasis during early embryogenesis. The aim of this work was to study the effect of 2-chloro-3-hydroxy-1,4-naphthoquinone, 2-chloro-3-(3-oxo-3-(piperidine-1-yl)propylamine)-1,4-naphthoquinone (FO-1), 2-chloro-3-(3-(morpholine-4-yl)-3-oxopropylamine)-1,4-naphthoquinone (FO-2 at concentrations of 10-3, 10-5, 10-7 M on the content of TBA-reactive substances (a byproduct of lipid peroxidation) and the activities of superoxide dismutase and catalase in loach embryos. It was established that 1,4-naphthoquinone amide derivatives and 2-chloro-3-hydroxy-1,4-naphthoquinone decreased the content of lipid peroxidation products in embryo cells in a dose-dependent manner. The investigated compounds cause an increase in superoxide dismutase and catalase activities compared with the control value. The results of the two-factor ANOVA test indicate that 2-chloro-3-hydroxy-1,4-naphthoquinone and 1,4-naphthoquinone amide derivatives (FO-1, FO-2) have predominant influence on the TBA-reactive substances content and superoxide dismutase activity. However, the time of loach embryos development has a more pronounced effect on catalase activity than the studied 1,4-naphthoquinone derivatives.
[Mh] Termos MeSH primário: Amidas/farmacologia
Antineoplásicos/farmacologia
Desenvolvimento Embrionário/efeitos dos fármacos
Naftoquinonas/farmacologia
[Mh] Termos MeSH secundário: Amidas/síntese química
Animais
Antineoplásicos/síntese química
Catalase/metabolismo
Cipriniformes
Relação Dose-Resposta a Droga
Embrião não Mamífero
Peroxidação de Lipídeos/efeitos dos fármacos
Fígado/efeitos dos fármacos
Fígado/enzimologia
Fígado/crescimento & desenvolvimento
Naftoquinonas/síntese química
Superóxido Dismutase/metabolismo
Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amides); 0 (Antineoplastic Agents); 0 (Naphthoquinones); 0 (Thiobarbituric Acid Reactive Substances); EC 1.11.1.6 (Catalase); EC 1.15.1.1 (Superoxide Dismutase)
[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:171214
[St] Status:MEDLINE
[do] DOI:10.15407/ubj88.03.046



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