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[PMID]:28920959
[Au] Autor:Kuntz EM; Baquero P; Michie AM; Dunn K; Tardito S; Holyoake TL; Helgason GV; Gottlieb E
[Ad] Endereço:Cancer Research UK, Beatson Institute, Glasgow, UK.
[Ti] Título:Targeting mitochondrial oxidative phosphorylation eradicates therapy-resistant chronic myeloid leukemia stem cells.
[So] Source:Nat Med;23(10):1234-1240, 2017 Oct.
[Is] ISSN:1546-170X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Treatment of chronic myeloid leukemia (CML) with imatinib mesylate and other second- and/or third-generation c-Abl-specific tyrosine kinase inhibitors (TKIs) has substantially extended patient survival. However, TKIs primarily target differentiated cells and do not eliminate leukemic stem cells (LSCs). Therefore, targeting minimal residual disease to prevent acquired resistance and/or disease relapse requires identification of new LSC-selective target(s) that can be exploited therapeutically. Considering that malignant transformation involves cellular metabolic changes, which may in turn render the transformed cells susceptible to specific assaults in a selective manner, we searched for such vulnerabilities in CML LSCs. We performed metabolic analyses on both stem cell-enriched (CD34 and CD34 CD38 ) and differentiated (CD34 ) cells derived from individuals with CML, and we compared the signature of these cells with that of their normal counterparts. Through combination of stable isotope-assisted metabolomics with functional assays, we demonstrate that primitive CML cells rely on upregulated oxidative metabolism for their survival. We also show that combination treatment with imatinib and tigecycline, an antibiotic that inhibits mitochondrial protein translation, selectively eradicates CML LSCs both in vitro and in a xenotransplantation model of human CML. Our findings provide a strong rationale for investigation of the use of TKIs in combination with tigecycline to treat patients with CML with minimal residual disease.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Mesilato de Imatinib/farmacologia
Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico
Minociclina/análogos & derivados
Mitocôndrias/efeitos dos fármacos
Células-Tronco Neoplásicas/efeitos dos fármacos
Fosforilação Oxidativa/efeitos dos fármacos
Inibidores de Proteínas Quinases/farmacologia
[Mh] Termos MeSH secundário: Animais
Western Blotting
Sobrevivência Celular/efeitos dos fármacos
Cromatografia Líquida
Quimioterapia Combinada
Feminino
Seres Humanos
Hipoglicemiantes/farmacologia
Mesilato de Imatinib/uso terapêutico
Técnicas In Vitro
Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo
Espectrometria de Massas
Metabolômica
Camundongos
Camundongos Endogâmicos NOD
Minociclina/farmacologia
Mitocôndrias/metabolismo
Células-Tronco Neoplásicas/metabolismo
Fenformin/farmacologia
Inibidores de Proteínas Quinases/uso terapêutico
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Células Tumorais Cultivadas
Ensaio Tumoral de Célula-Tronco
Regulação para Cima
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Hypoglycemic Agents); 0 (Protein Kinase Inhibitors); 70JE2N95KR (tigecycline); 8A1O1M485B (Imatinib Mesylate); DD5K7529CE (Phenformin); FYY3R43WGO (Minocycline)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170919
[St] Status:MEDLINE
[do] DOI:10.1038/nm.4399


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[PMID]:28550180
[Au] Autor:Xu Y; Gray A; Hardie DG; Uzun A; Shaw S; Padbury J; Phornphutkul C; Tseng YT
[Ad] Endereço:Women & Infants Hospital of Rhode Island, Providence, Rhode Island.
[Ti] Título:A novel, de novo mutation in the gene: infantile-onset phenotype and the signaling pathway involved.
[So] Source:Am J Physiol Heart Circ Physiol;313(2):H283-H292, 2017 Aug 01.
[Is] ISSN:1522-1539
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:encodes the γ -subunit isoform of 5'-AMP-activated protein kinase (AMPK), a heterotrimeric enzyme with major roles in the regulation of energy metabolism in response to cellular stress. Mutations in have been implicated in a unique hypertrophic cardiomyopathy (HCM) characterized by cardiac glycogen overload, ventricular preexcitation, and hypertrophy. We identified a novel, de novo mutation (K475E) in a neonate with prenatal onset of HCM. We aimed to investigate the cellular impact, signaling pathways involved, and therapeutic options for K475E mutation using cells stably expressing human wild-type (WT) or the K475E mutant. In human embryonic kidney-293 cells, the K475E mutation induced a marked increase in the basal phosphorylation of T172 and AMPK activity, reduced sensitivity to AMP in allosteric activation, and a loss of response to phenformin. In H9c2 cardiomyocytes, the K475E mutation induced inhibition of AMPK and reduced the response to phenformin and increases in the phosphorylation of p70S6 kinase (p70S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). Primary fibroblasts from the patient with the K475E mutation also showed marked increases in the phosphorylation of p70S6K and 4E-BP1 compared with those from age-matched, nondiseased controls. Moreover, overexpression of K475E induced hypertrophy in H9c2 cells, which was effectively reversed by treatment with rapamycin. Taken together, we have identified a novel, de novo infantile-onset mutation causing HCM. Our study suggests the K475E mutation induces alteration in basal AMPK activity and results in a hypertrophy phenotype involving the mechanistic target of rapamycin signaling pathway, which can be reversed with rapamycin. We identified a novel, de novo mutation (K475E) in the cystathionine ß-synthase 3 repeat, a region critical for AMP binding but with no previous reported mutation. Our data suggest the mutation affects AMP-activated protein kinase activity, activates cell growth pathways, and results in cardiac hypertrophy, which can be reversed with rapamycin.
[Mh] Termos MeSH primário: Proteínas Quinases Ativadas por AMP/genética
Cardiomiopatia Hipertrófica/genética
Mutação de Sentido Incorreto
Miócitos Cardíacos/enzimologia
Transdução de Sinais
[Mh] Termos MeSH secundário: Proteínas Quinases Ativadas por AMP/química
Proteínas Quinases Ativadas por AMP/metabolismo
Monofosfato de Adenosina/metabolismo
Cardiomiopatia Hipertrófica/tratamento farmacológico
Cardiomiopatia Hipertrófica/enzimologia
Cardiomiopatia Hipertrófica/fisiopatologia
Proteínas de Transporte/metabolismo
Estudos de Casos e Controles
Análise Mutacional de DNA
Ativação Enzimática
Fibroblastos/enzimologia
Fibroblastos/patologia
Predisposição Genética para Doença
Células HEK293
Seres Humanos
Recém-Nascido
Modelos Moleculares
Miócitos Cardíacos/efeitos dos fármacos
Miócitos Cardíacos/patologia
Fenformin/farmacologia
Fenótipo
Fosfoproteínas/metabolismo
Fosforilação
Conformação Proteica
Inibidores de Proteínas Quinases/farmacologia
Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo
Transdução de Sinais/efeitos dos fármacos
Sirolimo/farmacologia
Relação Estrutura-Atividade
Serina-Treonina Quinases TOR/antagonistas & inibidores
Serina-Treonina Quinases TOR/metabolismo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Eif4ebp1 protein, rat); 0 (Phosphoproteins); 0 (Protein Kinase Inhibitors); 415SHH325A (Adenosine Monophosphate); DD5K7529CE (Phenformin); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (PRKAG2 protein, human); EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa); EC 2.7.11.31 (AMP-Activated Protein Kinases); W36ZG6FT64 (Sirolimus)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170528
[St] Status:MEDLINE
[do] DOI:10.1152/ajpheart.00813.2016


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[PMID]:28433543
[Au] Autor:Kim SH; Li M; Trousil S; Zhang Y; Pasca di Magliano M; Swanson KD; Zheng B
[Ad] Endereço:Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
[Ti] Título:Phenformin Inhibits Myeloid-Derived Suppressor Cells and Enhances the Anti-Tumor Activity of PD-1 Blockade in Melanoma.
[So] Source:J Invest Dermatol;137(8):1740-1748, 2017 Aug.
[Is] ISSN:1523-1747
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Biguanides, such as the diabetes therapeutics metformin and phenformin, have shown antitumor activity both in vitro and in vivo. However, their potential effects on the tumor microenvironment are largely unknown. Here we report that phenformin selectively inhibits granulocytic myeloid-derived suppressor cells in spleens of tumor-bearing mice and ex vivo. Phenformin induces production of reactive oxygen species in granulocytic myeloid-derived suppressor cells, whereas the antioxidant N-acetylcysteine attenuates the inhibitory effects of phenformin. Co-treatment of phenformin enhances the effect of anti-PD-1 antibody therapy on inhibiting tumor growth in the BRAF V600E/PTEN-null melanoma mouse model. Combination of phenformin and anti PD-1 cooperatively induces CD8 T-cell infiltration and decreases levels of proteins that are critical for immune suppressive activities of myeloid-derived suppressor cells. Our findings show a selective, inhibitory effect of phenformin on granulocytic myeloid-derived suppressor cell-driven immune suppression and support that phenformin improves the anti-tumor activity of PD-1 blockade immunotherapy in melanoma.
[Mh] Termos MeSH primário: Melanoma/tratamento farmacológico
Células Supressoras Mieloides/efeitos dos fármacos
Neoplasias Experimentais
Fenformin/farmacologia
Receptor de Morte Celular Programada 1/antagonistas & inibidores
Neoplasias Cutâneas/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Feminino
Citometria de Fluxo
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Hipoglicemiantes/farmacologia
Imuno-Histoquímica
Imunoterapia
Melanoma/metabolismo
Melanoma/patologia
Camundongos
Células Supressoras Mieloides/metabolismo
Células Supressoras Mieloides/patologia
Receptor de Morte Celular Programada 1/biossíntese
Receptor de Morte Celular Programada 1/genética
RNA Neoplásico/genética
Reação em Cadeia da Polimerase em Tempo Real
Neoplasias Cutâneas/metabolismo
Neoplasias Cutâneas/patologia
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hypoglycemic Agents); 0 (Pdcd1 protein, mouse); 0 (Programmed Cell Death 1 Receptor); 0 (RNA, Neoplasm); DD5K7529CE (Phenformin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170913
[Lr] Data última revisão:
170913
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170424
[St] Status:MEDLINE


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[PMID]:28143781
[Au] Autor:Trousil S; Chen S; Mu C; Shaw FM; Yao Z; Ran Y; Shakuntala T; Merghoub T; Manstein D; Rosen N; Cantley LC; Zippin JH; Zheng B
[Ad] Endereço:Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
[Ti] Título:Phenformin Enhances the Efficacy of ERK Inhibition in NF1-Mutant Melanoma.
[So] Source:J Invest Dermatol;137(5):1135-1143, 2017 May.
[Is] ISSN:1523-1747
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Inactivation of the tumor suppressor neurofibromin 1 (NF1) presents a newly characterized melanoma subtype, for which currently no targeted therapies are clinically available. Preclinical studies suggest that extracellular signal-regulated kinase (ERK) inhibitors are likely to provide benefit, albeit with limited efficacy as a single agent; therefore, there is a need for rationally designed combination therapies. Here, we evaluate the combination of the ERK inhibitor SCH772984 and the biguanide phenformin. A combination of both compounds showed potent synergy in cell viability assays and cooperatively induced apoptosis. Treatment with both drugs was required to fully suppress mechanistic target of rapamycin signaling, a known effector of NF1 loss. Mechanistically, SCH772984 increased the oxygen consumption rate, indicating that these cells relied more on oxidative phosphorylation upon treatment. Consistently, SCH772984 increased expression of the mitochondrial transcriptional coactivator peroxisome proliferator-activated receptor gamma, coactivator 1-α. In contrast, cotreatment with phenformin, an inhibitor of complex I of the respiratory chain, decreased the oxygen consumption rate. SCH772984 also promoted the expansion of the H3K4 demethylase KDM5B (also known as JARID1B)-positive subpopulation of melanoma cells, which are slow-cycling and treatment-resistant. Importantly, phenformin suppressed this KDM5B-positive population, which reduced the emergence of SCH772984-resistant clones in long-term cultures. Our results warrant the clinical investigation of this combination therapy in patients with NF1 mutant melanoma.
[Mh] Termos MeSH primário: MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores
Indazóis/farmacologia
Melanoma/tratamento farmacológico
Neurofibromina 1/genética
Fenformin/farmacologia
Piperazinas/farmacologia
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Sinergismo Farmacológico
Seres Humanos
Indazóis/administração & dosagem
Melanoma/genética
Melanoma/patologia
Mutação
Consumo de Oxigênio/efeitos dos fármacos
Fenformin/administração & dosagem
Piperazinas/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Indazoles); 0 (Neurofibromin 1); 0 (Piperazines); 0 (SCH772984); DD5K7529CE (Phenformin); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170202
[St] Status:MEDLINE
[do] DOI:10.1016/j.jid.2017.01.013


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[PMID]:27792451
[Au] Autor:Liu X; Gan B
[Ad] Endereço:a Department of Experimental Radiation Oncology , University of Texas MD Anderson Cancer Center , Houston , TS , USA.
[Ti] Título:lncRNA NBR2 modulates cancer cell sensitivity to phenformin through GLUT1.
[So] Source:Cell Cycle;15(24):3471-3481, 2016 Dec 16.
[Is] ISSN:1551-4005
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Biguanides, including metformin (widely used in diabetes treatment) and phenformin, are AMP-activated protein kinase (AMPK) activators and potential drugs for cancer treatment. A more in-depth understanding of how cancer cells adapt to biguanide treatment may provide important therapeutic implications to achieve more effective and rational cancer therapies. NBR2 is a glucose starvation-induced long non-coding RNA (lncRNA) that interacts with AMPK and regulates AMPK activity upon glucose starvation. Here we show that phenformin treatment induces NBR2 expression, and NBR2 deficiency sensitizes cancer cells to phenformin-induced cell death. Surprisingly, unlike glucose starvation, phenformin does not induce NBR2 interaction with AMPK, and correspondingly, NBR2 deficiency does not affect phenformin-induced AMPK activation. We further reveal that NBR2 depletion attenuates phenformin-induced glucose transporter GLUT1 expression and glucose uptake. GLUT1 deficiency sensitizes cancer cells to phenformin-induced cell death, whereas GLUT1 restoration in NBR2 deficient cells rescues the increased cell death upon phenformin treatment. Together, the results of our study reveal that NBR2-GLUT1 axis may serve as an adaptive response in cancer cells to survive in response to phenformin treatment, and identify a novel mechanism coupling lncRNA to biguanide-mediated biology.
[Mh] Termos MeSH primário: Transportador de Glucose Tipo 1/metabolismo
Neoplasias/genética
Neoplasias/patologia
Fenformin/farmacologia
RNA Longo não Codificante/metabolismo
[Mh] Termos MeSH secundário: Proteínas Quinases Ativadas por AMP/metabolismo
Morte Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Ativação Enzimática/efeitos dos fármacos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Glucose/metabolismo
Células HEK293
Seres Humanos
Alvo Mecanístico do Complexo 1 de Rapamicina
Complexos Multiproteicos/metabolismo
RNA Longo não Codificante/genética
Frações Subcelulares/efeitos dos fármacos
Frações Subcelulares/metabolismo
Serina-Treonina Quinases TOR/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Glucose Transporter Type 1); 0 (Multiprotein Complexes); 0 (NBR2 long noncoding RNA, human); 0 (RNA, Long Noncoding); 0 (SLC2A1 protein, human); DD5K7529CE (Phenformin); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1); EC 2.7.11.31 (AMP-Activated Protein Kinases); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161030
[St] Status:MEDLINE
[do] DOI:10.1080/15384101.2016.1249545


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[PMID]:27506389
[Au] Autor:Bridges HR; Sirviö VA; Agip AN; Hirst J
[Ad] Endereço:Medical Research Council Mitochondrial Biology Unit, Wellcome Trust / MRC Building, Hills Road, Cambridge, CB2 0XY, UK.
[Ti] Título:Molecular features of biguanides required for targeting of mitochondrial respiratory complex I and activation of AMP-kinase.
[So] Source:BMC Biol;14:65, 2016 Aug 09.
[Is] ISSN:1741-7007
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The biguanides are a family of drugs with diverse clinical applications. Metformin, a widely used anti-hyperglycemic biguanide, suppresses mitochondrial respiration by inhibiting respiratory complex I. Phenformin, a related anti-hyperglycemic biguanide, also inhibits respiration, but proguanil, which is widely used for the prevention of malaria, does not. The molecular structures of phenformin and proguanil are closely related and both inhibit isolated complex I. Proguanil does not inhibit respiration in cells and mitochondria because it is unable to access complex I. The molecular features that determine which biguanides accumulate in mitochondria, enabling them to inhibit complex I in vivo, are not known. RESULTS: Here, a family of seven biguanides are used to reveal the molecular features that determine why phenformin enters mitochondria and inhibits respiration whereas proguanil does not. All seven biguanides inhibit isolated complex I, but only four of them inhibit respiration in cells and mitochondria. Direct conjugation of a phenyl group and bis-substitution of the biguanide moiety prevent uptake into mitochondria, irrespective of the compound hydrophobicity. This high selectivity suggests that biguanide uptake into mitochondria is protein mediated, and is not by passive diffusion. Only those biguanides that enter mitochondria and inhibit complex I activate AMP kinase, strengthening links between complex I and the downstream effects of biguanide treatments. CONCLUSIONS: Biguanides inhibit mitochondrial complex I, but specific molecular features control the uptake of substituted biguanides into mitochondria, so only some biguanides inhibit mitochondrial respiration in vivo. Biguanides with restricted intracellular access may be used to determine physiologically relevant targets of biguanide action, and for the rational design of substituted biguanides for diverse clinical applications.
[Mh] Termos MeSH primário: Adenilato Quinase/metabolismo
Biguanidas/química
Biguanidas/farmacologia
Complexo I de Transporte de Elétrons/metabolismo
[Mh] Termos MeSH secundário: Animais
Bovinos
Linhagem Celular Tumoral
Permeabilidade da Membrana Celular/efeitos dos fármacos
Respiração Celular/efeitos dos fármacos
Ativação Enzimática/efeitos dos fármacos
Camundongos
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/metabolismo
Membranas Mitocondriais/efeitos dos fármacos
Membranas Mitocondriais/metabolismo
Consumo de Oxigênio/efeitos dos fármacos
Fenformin/farmacologia
Ratos
Rotenona/farmacologia
Solubilidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biguanides); 03L9OT429T (Rotenone); DD5K7529CE (Phenformin); EC 1.6.5.3 (Electron Transport Complex I); EC 2.7.4.3 (Adenylate Kinase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160811
[St] Status:MEDLINE
[do] DOI:10.1186/s12915-016-0287-9


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[PMID]:27392906
[Au] Autor:Oh-Hashi K; Irie N; Sakai T; Okuda K; Nagasawa H; Hirata Y; Kiuchi K
[Ad] Endereço:Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan. oohashi@gifu-u.ac.jp.
[Ti] Título:Elucidation of a novel phenformin derivative on glucose-deprived stress responses in HT-29 cells.
[So] Source:Mol Cell Biochem;419(1-2):29-40, 2016 Aug.
[Is] ISSN:1573-4919
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Recently, we developed a variety of phenformin derivatives as selective antitumor agents. Based on previous findings, this study evaluated a promising compound, 2-(2-chlorophenyl)ethylbiguanide (2-Cl-Phen), on the basis of stress responses in the human colon cancer cell line HT-29 under a serum- and glucose-deprived condition. 2-Cl-Phen triggered morphological changes such as shrinkage and plasma membrane disintegration, as well as a decrease in mitochondrial activity and an increase in LDH leakage. To understand intracellular issues relating to 2-Cl-Phen, this study focused on the expression levels of ER stress-inducible genes and several oncogenic genes. Serum and glucose deprivation significantly induced a variety of ER stress-inducible genes, but a 12-h treatment of 2-Cl-Phen down-regulated expression of several ER stress-related genes, with the exception of GADD153. Interestingly, the expression levels of ATF6α, GRP78, MANF, and CRELD2 mRNA were almost completely decreased by 2-Cl-Phen. This study also observed that a 24-h treatment of 2-Cl-Phen attenuated the expression levels of GRP78, GADD153, and c-Myc protein. The decrease in c-Myc protein occurred before the fluctuation of GRP78 protein, while the expression of c-Myc mRNA showed little change with cotreatment of serum and glucose deprivation with 2-Cl-Phen. To further understand the 2-Cl-Phen-induced down-regulation of ATF6-related genes, this study investigated the stability of ATF6α and GRP78 proteins using NanoLuc-tagged constructs. The expression levels of NanoLuc-tagged ATF6α and GRP78 were significantly down-regulated by 2-Cl-Phen in the presence or absence of the translation inhibitor cycloheximide. Taken together, our novel phenformin derivative 2-Cl-Phen has the unique characteristic of diminishing tumor adaptive responses, especially the expression of ATF6-related genes, as well as that of c-Myc protein, in a transcriptional and posttranscriptional manner under a serum- and glucose-deprived condition. Further characterization of cytotoxic mechanisms related to phenformin derivatives may give new insights into developing additional promising anticancer agents.
[Mh] Termos MeSH primário: Neoplasias do Colo/metabolismo
Estresse do Retículo Endoplasmático/efeitos dos fármacos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Glucose
Proteínas de Neoplasias/biossíntese
Fenformin
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Neoplasias do Colo/patologia
Seres Humanos
Fenformin/análogos & derivados
Fenformin/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Neoplasm Proteins); DD5K7529CE (Phenformin); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160710
[St] Status:MEDLINE
[do] DOI:10.1007/s11010-016-2747-5


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[PMID]:27328723
[Au] Autor:Ohnishi S; Mizutani H; Kawanishi S
[Ad] Endereço:a Faculty of Pharmaceutical Sciences , Suzuka University of Medical Science , Suzuka , Mie , Japan ;
[Ti] Título:The enhancement of oxidative DNA damage by anti-diabetic metformin, buformin, and phenformin, via nitrogen-centered radicals.
[So] Source:Free Radic Res;50(8):929-37, 2016 Aug.
[Is] ISSN:1029-2470
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Metformin (N,N-dimethylbiguanide), buformin (1-butylbiguanide), and phenformin (1-phenethylbiguanide) are anti-diabetic biguanide drugs, expected to having anti-cancer effect. The mechanism of anti-cancer effect by these drugs is not completely understood. In this study, we demonstrated that these drugs dramatically enhanced oxidative DNA damage under oxidative condition. Metformin, buformin, and phenformin enhanced generation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in isolated DNA reacted with hydrogen peroxide (H2O2) and Cu(II), although these drugs did not form 8-oxodG in the absence of H2O2 or Cu(II). An electron paramagnetic resonance (EPR) study, utilizing alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone and 3,3,5,5-tetramethyl-1-pyrroline-N-oxide as spin trapping agents, showed that nitrogen-centered radicals were generated from biguanides in the presence of Cu(II) and H2O2, and that these radicals were decreased by the addition of DNA. These results suggest that biguanides enhance Cu(II)/H2O2-mediated 8-oxodG generation via nitrogen-centered radical formation. The enhancing effect on oxidative DNA damage may play a role on anti-cancer activity.
[Mh] Termos MeSH primário: Buformina/farmacologia
Dano ao DNA/efeitos dos fármacos
Hipoglicemiantes/farmacologia
Metformina/farmacologia
Fenformin/farmacologia
[Mh] Termos MeSH secundário: Animais
Buformina/administração & dosagem
Bovinos
Dano ao DNA/genética
Seres Humanos
Hipoglicemiantes/administração & dosagem
Metformina/administração & dosagem
Oxirredução
Fenformin/administração & dosagem
Espécies Reativas de Oxigênio
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hypoglycemic Agents); 0 (Reactive Oxygen Species); 9100L32L2N (Metformin); DD5K7529CE (Phenformin); W2115E9C7B (Buformin)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170224
[Lr] Data última revisão:
170224
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160623
[St] Status:MEDLINE
[do] DOI:10.1080/10715762.2016.1204651


  9 / 1249 MEDLINE  
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[PMID]:27159954
[Au] Autor:Safonova OA; Popova TN; Kryl'skii DV
[Ti] Título:[GLUTATHIONE SYSTEM ACTIVITY IN RAT TISSUES UNDER PHENYLETHYL BIGUANIDE ACTION ON THE BACKGROUND OF EXPERIMENTAL BRAIN ISCHEMIA/REPERFUSION DEVELOPMENT].
[So] Source:Eksp Klin Farmakol;79(1):23-7, 2016.
[Is] ISSN:0869-2092
[Cp] País de publicação:Russia (Federation)
[La] Idioma:rus
[Ab] Resumo:It was studied the total antioxidant activity, content of primary lipid peroxidation (LPO) products and reduced glutathione, and the activity of glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase, and NADP-isocitrate dehydrogenase in rat tissues under phenylethyl biguanide (phenfor- min) action on the background of experimental brain ischemia/reperfusion development. It is stablished the analyzed parameters, increasing under ischemia/reperfusion conditions in the brain and blood serum of animals, exhibit a decrease upon the introduction of this biguanide derivative. The obtained data can be explained by a decrease in degree of mobilization of the antioxidant system--in particular, of its glutathione chain--in the pathologic state. Hence, there is a need in NADPH supply for the system functioning compared with the pathology. Thus, phenylethyl biguanide demonstrates its antioxidant and protective properties under oxidative stress development that is accompanied by accumulation of the products of free radical oxidation of biomolecules during the ischemic brain injury.
[Mh] Termos MeSH primário: Antioxidantes/farmacologia
Lesões Encefálicas
Glutationa/metabolismo
Fenformin/farmacologia
Traumatismo por Reperfusão
[Mh] Termos MeSH secundário: Animais
Lesões Encefálicas/tratamento farmacológico
Lesões Encefálicas/metabolismo
Radicais Livres/metabolismo
Peroxidação de Lipídeos/efeitos dos fármacos
Estresse Oxidativo/efeitos dos fármacos
Oxirredutases/metabolismo
Ratos
Traumatismo por Reperfusão/tratamento farmacológico
Traumatismo por Reperfusão/metabolismo
[Pt] Tipo de publicação:ENGLISH ABSTRACT; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antioxidants); 0 (Free Radicals); DD5K7529CE (Phenformin); EC 1.- (Oxidoreductases); GAN16C9B8O (Glutathione)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:160510
[Lr] Data última revisão:
160510
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160511
[St] Status:MEDLINE


  10 / 1249 MEDLINE  
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[PMID]:27069123
[Au] Autor:Lea MA; Guzman Y; Desbordes C
[Ad] Endereço:Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ, U.S.A. lea@njms.rutgers.edu.
[Ti] Título:Inhibition of Growth by Combined Treatment with Inhibitors of Lactate Dehydrogenase and either Phenformin or Inhibitors of 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase 3.
[So] Source:Anticancer Res;36(4):1479-88, 2016 Apr.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:Enhanced glycolysis in cancer cells presents a target for chemotherapy. Previous studies have indicated that proliferation of cancer cells can be inhibited by treatment with phenformin and with an inhibitor of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB) namely 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO). In the present work, the action of two inhibitors that are effective at lower concentrations than 3PO, namely 1-(3-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PQP) and 1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PFK15) were investigated. The inhibitors of lactate dehydrogenase (LDHA) studied in order of half-maximal inhibitory concentrations were methyl 1-hydroxy-6-phenyl-4-(trifluoromethyl)-1H-indole-2-carboxylate (NHI-2) < isosafrole < oxamate. In colonic and bladder cancer cells, additive growth inhibitory effects were seen with the LDHA inhibitors, of which NHI-2 was effective at the lowest concentrations. Growth inhibition was generally greater with PFK15 than with PQP. The increased acidification of the culture medium and glucose uptake caused by phenformin was blocked by combined treatment with PFKFB3 or LDHA inhibitors. The results suggest that combined treatment with phenformin and inhibitors of glycolysis can cause additive inhibition of cell proliferation and may mitigate lactic acidosis caused by phenformin when used as a single agent.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Hipoglicemiantes/farmacologia
L-Lactato Desidrogenase/antagonistas & inibidores
Fenformin/farmacologia
Fosfofrutoquinase-2/antagonistas & inibidores
Piridinas/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Glucose/metabolismo
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Hypoglycemic Agents); 0 (Pyridines); DD5K7529CE (Phenformin); EC 1.1.1.27 (L-Lactate Dehydrogenase); EC 2.7.1.105 (Phosphofructokinase-2); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:160412
[Lr] Data última revisão:
160412
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160413
[St] Status:MEDLINE



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