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1.
Int J Mol Sci ; 22(17)2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34502300

RESUMO

Folate depletion causes chromosomal instability by increasing DNA strand breakage, uracil misincorporation, and defective repair. Folate mediated one-carbon metabolism has been suggested to play a key role in the carcinogenesis and progression of hepatocellular carcinoma (HCC) through influencing DNA integrity. Methylenetetrahydrofolate reductase (MTHFR) is the enzyme catalyzing the irreversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate that can control folate cofactor distributions and modulate the partitioning of intracellular one-carbon moieties. The association between MTHFR polymorphisms and HCC risk is inconsistent and remains controversial in populational studies. We aimed to establish an in vitro cell model of liver origin to elucidate the interactions between MTHFR function, folate status, and chromosome stability. In the present study, we (1) examined MTHFR expression in HCC patients; (2) established cell models of liver origin with stabilized inhibition of MTHFR using small hairpin RNA delivered by a lentiviral vector, and (3) investigated the impacts of reduced MTHFR and folate status on cell cycle, methyl group homeostasis, nucleotide biosynthesis, and DNA stability, all of which are pathways involved in DNA integrity and repair and are critical in human tumorigenesis. By analyzing the TCGA/GTEx datasets available within GEPIA2, we discovered that HCC cancer patients with higher MTHFR had a worse survival rate. The shRNA of MTHFR (shMTHFR) resulted in decreased MTHFR gene expression, MTHFR protein, and enzymatic activity in human hepatoma cell HepG2. shMTHFR tended to decrease intracellular S-adenosylmethionine (SAM) contents but folate depletion similarly decreased SAM in wildtype (WT), negative control (Neg), and shMTHFR cells, indicating that in cells of liver origin, shMTHFR does not exacerbate the methyl group supply in folate depletion. shMTHFR caused cell accumulations in the G2/M, and cell population in the G2/M was inversely correlated with MTHFR gene level (r = -0.81, p < 0.0001), MTHFR protein expression (r = -0.8; p = 0.01), and MTHFR enzyme activity (r = -0.842; p = 0.005). Folate depletion resulted in G2/M cell cycle arrest in WT and Neg but not in shMTHFR cells, indicating that shMTHFR does not exacerbate folate depletion-induced G2/M cell cycle arrest. In addition, shMTHFR promoted the expression and translocation of nuclei thymidine synthetic enzyme complex SHMT1/DHFR/TYMS and assisted folate-dependent de novo nucleotide biosynthesis under folate restriction. Finally, shMTHFR promoted nuclear MLH1/p53 expression under folate deficiency and further reduced micronuclei formation and DNA uracil misincorporation under folate deficiency. In conclusion, shMTHFR in HepG2 induces cell cycle arrest in G2/M that may promote nucleotide supply and assist cell defense against folate depletion-induced chromosome segregation and uracil misincorporation in the DNA. This study provided insight into the significant impact of MTHFR function on chromosome stability of hepatic tissues. Data from the present study may shed light on the potential regulatory mechanism by which MTHFR modulates the risk for hepatic malignancies.


Assuntos
Carcinoma Hepatocelular/patologia , Segregação de Cromossomos , DNA de Neoplasias/genética , Ácido Fólico/metabolismo , Metilenotetra-Hidrofolato Redutase (NADPH2)/antagonistas & inibidores , Uracila/metabolismo , Apoptose , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proliferação de Células , Instabilidade Cromossômica , DNA de Neoplasias/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Polimorfismo Genético , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas
2.
Biochimie ; 183: 100-107, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33476699

RESUMO

The folate and methionine cycles, constituting one-carbon metabolism, are critical pathways for cell survival. Intersecting these two cycles, 5,10-methylenetetrahydrofolate reductase (MTHFR) directs one-carbon units from the folate to methionine cycle, to be exclusively used for methionine and S-adenosylmethionine (AdoMet) synthesis. MTHFR deficiency and upregulation result in diverse disease states, rendering it an attractive drug target. The activity of MTHFR is inhibited by the binding of AdoMet to an allosteric regulatory domain distal to the enzyme's active site, which we have previously identified to constitute a novel fold with a druggable pocket. Here, we screened 162 AdoMet mimetics using differential scanning fluorimetry, and identified 4 compounds that stabilized this regulatory domain. Three compounds were sinefungin analogues, closely related to AdoMet and S-adenosylhomocysteine (AdoHcy). The strongest thermal stabilisation was provided by (S)-SKI-72, a potent inhibitor originally developed for protein arginine methyltransferase 4 (PRMT4). Using surface plasmon resonance, we confirmed that (S)-SKI-72 binds MTHFR via its allosteric domain with nanomolar affinity. Assay of MTHFR activity in the presence of (S)-SKI-72 demonstrates inhibition of purified enzyme with sub-micromolar potency and endogenous MTHFR from HEK293 cell lysate in the low micromolar range, both of which are lower than AdoMet. Nevertheless, unlike AdoMet, (S)-SKI-72 is unable to completely abolish MTHFR activity, even at very high concentrations. Combining binding assays, kinetic characterization and compound docking, this work indicates the regulatory domain of MTHFR can be targeted by small molecules and presents (S)-SKI-72 as an excellent candidate for development of MTHFR inhibitors.


Assuntos
Inibidores Enzimáticos/química , Metilenotetra-Hidrofolato Redutase (NADPH2)/antagonistas & inibidores , Metilenotetra-Hidrofolato Redutase (NADPH2)/química , S-Adenosilmetionina/química , Regulação Alostérica , Humanos , Domínios Proteicos
3.
Cell Physiol Biochem ; 45(3): 1149-1155, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29444504

RESUMO

BACKGROUND/AIMS: The association between the genetic polymorphisms located in either the exon or untranslated region of MTHFR and the risk of human atherosclerosis has been well-documented. This study analyzed MTHFR polymorphisms at the 3'-untranslated region for association with risk and outcome of atherosclerosis in a Chinese Han population. METHODS: The hospital based case-control study was conducted with 500 patients and 600 healthy volunteers as control enrolled. The genotyping was conducted by using Taqman probe. The potential interaction was predicted by multiple bioinformatics analysis. The relative expression of MTHFR was detected by qRT-PCR. Further confirmation was determined by dual-luciferase assay. The plasma homocysteine levels were assayed by ELISA. RESULTS: Cigarette smoking, alcohol consumption, diabetes, hypertension and low levels of serum high-density lipoprotein-C were associated with an increased risk of developing ischemic stroke. MTHFR rs915014 AG and GG genotypes were significantly associated with increased risk of rs915014 compared with the GG genotype. The qRT-PCR confirmed that MTHFR rs915014 AG or GG genotypes could facilitate miR-2861 binding leading to decreased MTHFR levels in cells. In addition, patients carrying the MTHFR rs915014 AG or GG genotypes were associated with accumulation of circulating tHcy volume and a poor atherosclerosis consequence. CONCLUSIONS: This study demonstrates that the MTHFR rs915014 is associated with increased risk of atherosclerosis and might be a shot term outcome biomarker for atherosclerosis patients.


Assuntos
Aterosclerose/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , MicroRNAs/metabolismo , Idoso , Consumo de Bebidas Alcoólicas , Antagomirs/metabolismo , Grupo com Ancestrais do Continente Asiático/genética , Aterosclerose/patologia , Estudos de Casos e Controles , Feminino , Células HEK293 , Homocisteína/sangue , Humanos , Hipertensão/complicações , Lipoproteínas HDL/sangue , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/antagonistas & inibidores , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fumar , Acidente Vascular Cerebral/etiologia
4.
Artigo em Inglês | MEDLINE | ID: mdl-29367024

RESUMO

The experimental and theoretical investigations of structure of the 3-(1-(phenylamino)ethylidene)-chroman-2,4-dione were performed. X-ray structure analysis and spectroscopic methods (FTIR and FT-Raman, 1H and 13C NMR), along with the density functional theory calculations (B3LYP functional with empirical dispersion corrections D3BJ in combination with the 6-311 + G(d,p) basis set), were used in order to characterize the molecular structure and spectroscopic behavior of the investigated coumarin derivative. Molecular docking analysis was carried out to identify the potency of inhibition of the title molecule against human's Ubiquinol-Cytochrome C Reductase Binding Protein (UQCRB) and Methylenetetrahydrofolate reductase (MTHFR). The inhibition activity was obtained for ten conformations of ligand inside the proteins.


Assuntos
Cromanos/química , Cromanos/farmacologia , Espectroscopia de Ressonância Magnética/métodos , Simulação de Acoplamento Molecular , Teoria Quântica , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Análise Espectral Raman/métodos , Proteínas de Transporte/antagonistas & inibidores , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/antagonistas & inibidores , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Termodinâmica
5.
Biochem Biophys Res Commun ; 465(3): 363-7, 2015 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-26253470

RESUMO

Genistein (5, 7-dihydroxy-3- (4-hydroxyphenyl)-4H-1-benzopyran-4-one) is a natural isoflavone revealing many biological activities. Thus, it is considered as a therapeutic compound in as various disorders as cancer, infections and genetic diseases. Here, we demonstrate for the first time that genistein inhibits activities of bacterial methylenetetrahydrofolate reductase (MetF) and lactate dehydrogenase (LDH). Both enzymes use NADH as a substrate, and results of biochemical as well as molecular modeling studies with MetF suggest that genistein may interfere with binding of this dinucleotide to the enzyme. These results have implications for our understanding of biological functions of genistein and its effects on cellular metabolism.


Assuntos
Genisteína/química , L-Lactato Desidrogenase/antagonistas & inibidores , Metilenotetra-Hidrofolato Redutase (NADPH2)/antagonistas & inibidores , Modelos Químicos , NAD/química , Sítios de Ligação , Ativação Enzimática , Simulação de Acoplamento Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/química , Especificidade por Substrato
6.
Am J Clin Nutr ; 101(3): 646-58, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25733650

RESUMO

BACKGROUND: Increased consumption of folic acid is prevalent, leading to concerns about negative consequences. The effects of folic acid on the liver, the primary organ for folate metabolism, are largely unknown. Methylenetetrahydrofolate reductase (MTHFR) provides methyl donors for S-adenosylmethionine (SAM) synthesis and methylation reactions. OBJECTIVE: Our goal was to investigate the impact of high folic acid intake on liver disease and methyl metabolism. DESIGN: Folic acid-supplemented diet (FASD, 10-fold higher than recommended) and control diet were fed to male Mthfr(+/+) and Mthfr(+/-) mice for 6 mo to assess gene-nutrient interactions. Liver pathology, folate and choline metabolites, and gene expression in folate and lipid pathways were examined. RESULTS: Liver and spleen weights were higher and hematologic profiles were altered in FASD-fed mice. Liver histology revealed unusually large, degenerating cells in FASD Mthfr(+/-) mice, consistent with nonalcoholic fatty liver disease. High folic acid inhibited MTHFR activity in vitro, and MTHFR protein was reduced in FASD-fed mice. 5-Methyltetrahydrofolate, SAM, and SAM/S-adenosylhomocysteine ratios were lower in FASD and Mthfr(+/-) livers. Choline metabolites, including phosphatidylcholine, were reduced due to genotype and/or diet in an attempt to restore methylation capacity through choline/betaine-dependent SAM synthesis. Expression changes in genes of one-carbon and lipid metabolism were particularly significant in FASD Mthfr(+/-) mice. The latter changes, which included higher nuclear sterol regulatory element-binding protein 1, higher Srepb2 messenger RNA (mRNA), lower farnesoid X receptor (Nr1h4) mRNA, and lower Cyp7a1 mRNA, would lead to greater lipogenesis and reduced cholesterol catabolism into bile. CONCLUSIONS: We suggest that high folic acid consumption reduces MTHFR protein and activity levels, creating a pseudo-MTHFR deficiency. This deficiency results in hepatocyte degeneration, suggesting a 2-hit mechanism whereby mutant hepatocytes cannot accommodate the lipid disturbances and altered membrane integrity arising from changes in phospholipid/lipid metabolism. These preliminary findings may have clinical implications for individuals consuming high-dose folic acid supplements, particularly those who are MTHFR deficient.


Assuntos
Suplementos Nutricionais/envenenamento , Inibidores Enzimáticos/envenenamento , Ácido Fólico/envenenamento , Homocistinúria/etiologia , Metabolismo dos Lipídeos , Fígado/metabolismo , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Espasticidade Muscular/etiologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Animais , Regulação da Expressão Gênica , Heterozigoto , Homocistinúria/metabolismo , Homocistinúria/patologia , Homocistinúria/fisiopatologia , Lipogênese , Fígado/patologia , Fígado/fisiopatologia , Masculino , Metilação , Metilenotetra-Hidrofolato Redutase (NADPH2)/antagonistas & inibidores , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Mutantes , Espasticidade Muscular/metabolismo , Espasticidade Muscular/patologia , Espasticidade Muscular/fisiopatologia , Mutação , Tamanho do Órgão , Transtornos Psicóticos/etiologia , Transtornos Psicóticos/metabolismo , Transtornos Psicóticos/patologia , Transtornos Psicóticos/fisiopatologia , Organismos Livres de Patógenos Específicos
7.
Pharmacogenomics ; 9(9): 1195-206, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18781847

RESUMO

The 5,10-methylenetetrahydrofolate reductase (MTHFR) is a key enzyme for intracellular folate homeostasis and metabolism. Two common MTHFR polymorphisms, C677T and A1298C, which lead to an altered amino acid sequence, have been associated with a decreased enzyme activity and susceptibility to cancer suggesting that these genetic variants may modulate the risk of several malignancies. C667T, and to a lesser extent A1298C polymorphisms, are also reported to influence the cytotoxic effect of fluoropyrimidines and antifolates providing support for their pharmacogenetic role in predicting the efficacy and the toxicity in cancer and rheumatoid arthritis patients. A combined polymorphisms and haplotype analysis may result in a more effective approach than a single polymorphism one. Moreover gene-nutrient/environmental and gene-racial/ethnic interactions have been shown to affect the impact of these MTHFR genetic variants. Further well-designed studies are needed to clarify the role of MTHFR polymorphisms to derive dose adjustment recommendations on the basis of the patient's genotype.


Assuntos
Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Farmacogenética/tendências , Polimorfismo Genético/genética , Animais , Predisposição Genética para Doença , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/antagonistas & inibidores , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Neoplasias/enzimologia , Neoplasias/genética , Farmacogenética/métodos , Polimorfismo Genético/efeitos dos fármacos , Fatores de Risco
8.
Cell Biol Int ; 32(8): 879-87, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18486501

RESUMO

The present study aimed to investigate the effect of knocking-down methylenetetrahydrofolate reductase (MTHFR) on the survival of the human gastric cancer cell line MKN45. Antisense and small interfering RNA (siRNA) plasmids were used to target MTHFR in MKN45. Meanwhile, we also constructed a wild-type MTHFR plasmid to assess the effect of over-expression of this protein on cell viability. The knock-down of MTHFR decreased cell survival by approximately 30% compared to the control and resulted in cell cycle arrest at the G2 phase. These cells also had lower levels of c-myc compared to control cells, while over-expression of MTHFR increased cell proliferation and induced the down-regulation of p21WAF1 and hMLH1. Inhibiting MTHFR with either antisense or siRNA decreases the viability of methionine-dependent transformed gastric cancer cells and suggests that MTHFR inhibition may be a novel anticancer approach.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Metilenotetra-Hidrofolato Redutase (NADPH2)/antagonistas & inibidores , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Interferente Pequeno , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/patologia , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Vetores Genéticos , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Proteína 1 Homóloga a MutL , Plasmídeos , Neoplasias Gástricas/terapia , Transfecção
9.
Curr Pharm Des ; 14(11): 1143-50, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18473861

RESUMO

Tumor cells have an enhanced requirement for glucose, amino acids and DNA precursors. Since folates are required for the synthesis of thymidine and purines, the metabolism of folate has been exploited as an anti-cancer target for over 6 decades, with emphasis on the inhibition of DNA synthesis. However, folate is also used to generate methionine, which is essential for proliferation by virtue of its role in protein synthesis, polyamine synthesis and transmethylation reactions. Tumor-derived cell lines and human tumor xenografts have been shown to be methionine dependent i.e., they are unable to survive without methionine and are unable to efficiently utilize homocysteine, the immediate metabolic precursor of methionine. Since non-transformed cells are methionine-independent, the targeting of methionine metabolism presents an opportunity to selectively disrupt the unique metabolic networks in cancer cells. This chapter provides an overview of the critical role of folate and methionine metabolism in tumor cells and summarizes the current anti-folate and anti-methionine strategies to inhibit growth of transformed lines and tumors. We also present our work on the development of a novel anti-cancer target, methylenetetrahydrofolate reductase (MTHFR), a key enzyme of both folate and methionine metabolism. Our data demonstrate that antisense-mediated inhibition of MTHFR is associated with increased cytotoxicity in vitro and with decreased growth of tumors in vivo. These findings warrant further investigation of this enzyme and the methionine biosynthetic pathway in exploring new strategies for cancer chemotherapy.


Assuntos
Antineoplásicos/farmacologia , Metilenotetra-Hidrofolato Redutase (NADPH2)/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Animais , Ensaios Clínicos como Assunto , Sistemas de Liberação de Medicamentos , Ácido Fólico/metabolismo , Humanos , Metionina/metabolismo , Oligonucleotídeos Antissenso/farmacologia
10.
Int J Hematol ; 87(5): 451-458, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18365141

RESUMO

Polymorphism in 5,10-methylenetetrahydrofolate reductase (MTHFR), a central enzyme in folate metabolism, has been shown to affect the sensitivity of patients to folate-based drugs such as methotrexate. In this study, we investigated whether a common single nucleotide polymorphism at position 677 in the donor or recipient's MTHFR gene affects the risk for acute graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-identical sibling donors when the recipient receives prophylactic treatment with methotrexate for GVHD. MTHFR genotypes were determined in 159 recipients with a hematological disease and their donors using polymerase chain reaction-restriction fragment length polymorphism analysis of genomic DNA. The 677TT genotype, which encodes an enzyme with approximately 30% of the activity of the wild-type (677CC), was observed in 13% of patients and in 8% of normal donors. Multivariate analyses demonstrated a significant association between 677TT genotype in patients and a lower incidence of grade I-IV acute GVHD (relative risk, 0.35; 95% confidence interval, 0.13-0.95; P = 0.040). There was no association between the incidence of acute GVHD and the donor MTHFR genotypes. These results suggest that greater immunosuppression by methotrexate due to low MTHFR enzyme activity decreases the risk of acute GVHD in recipients of allogeneic HSCT.


Assuntos
Doença Enxerto-Hospedeiro/genética , Transplante de Células-Tronco Hematopoéticas , Doadores Vivos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético , Doença Aguda , Adolescente , Adulto , Feminino , Genótipo , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/enzimologia , Doenças Hematológicas/enzimologia , Doenças Hematológicas/genética , Doenças Hematológicas/terapia , Humanos , Imunossupressão/métodos , Imunossupressores/administração & dosagem , Masculino , Metotrexato/administração & dosagem , Metilenotetra-Hidrofolato Redutase (NADPH2)/antagonistas & inibidores , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Pessoa de Meia-Idade , Fatores de Risco , Transplante Homólogo
11.
Int J Oral Maxillofac Surg ; 36(5): 429-34, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17467239

RESUMO

Non-syndromic cleft of the lip and/or palate is one of the most common birth defects in humans. Embryonic palatal mesenchymal (EPM) cells are an attractive source for investigating embryonic palatal development. In this study, we developed a highly efficient transfection method for murine EPM (MEPM) cells. MEPM cells were transfected with the plasmid pEGFP-N1 using two non-viral methods: nucleofection and lipofection. Nucleofection provided a much better rate of gene transfer than lipofection particularly in MEPM cells. The methylenetetrahydrofolate reductase (MTHFR) gene is an important candidate for involvement in the pathogenesis of this birth defect. The RNA interference plasmid of MTHFR was constructed and nucleofected into MEPM cells. Successful transfection resulted in a remarkable reduction in the expression of MTHFR. Taken together, the results indicate that nucleofection is highly efficient for MEPM cell transfection, and that this approach may be useful for investigating gene function in the process of palatogenesis.


Assuntos
Células-Tronco Mesenquimais/fisiologia , Palato/embriologia , Transfecção/métodos , Animais , Western Blotting , Núcleo Celular , Células Cultivadas , Fissura Palatina/embriologia , Fissura Palatina/genética , Feminino , Corantes Fluorescentes , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas de Fluorescência Verde , Lipídeos , Lipossomos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/antagonistas & inibidores , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Plasmídeos/genética , Reação em Cadeia da Polimerase
12.
Mini Rev Med Chem ; 5(12): 1061-73, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16375752

RESUMO

1,4-Benzothiazine (1,4-BT) derivatives have been reported to exhibit a wide range of pharmacological properties including antifungal, immunostimulating, anti-aldoso-reductase, anti-rheumatic, anti-allergic, vasorelaxant, anti-arrhythmic, anti-hypertensive, neuroprotective and cytotoxic activities. These different effects indicate that 1,4-BT is a template potentially useful in medicinal chemistry research and therapeutic applications.


Assuntos
Tiazinas/química , Tiazinas/farmacologia , Antialérgicos/química , Antialérgicos/farmacologia , Antiarrítmicos/química , Antiarrítmicos/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Antirreumáticos/química , Antirreumáticos/farmacologia , Canais de Cálcio/metabolismo , Metilenotetra-Hidrofolato Redutase (NADPH2)/antagonistas & inibidores , Metilenotetra-Hidrofolato Redutase (NADPH2)/farmacologia , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Canais de Potássio/metabolismo , Vasodilatadores/química , Vasodilatadores/farmacologia
13.
Clin Cancer Res ; 11(5): 2047-52, 2005 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-15756031

RESUMO

PURPOSE: Many cancer lines are methionine dependent and decrease proliferation when methionine supply is limited. Methylenetetrahydrofolate reductase (MTHFR) generates the folate derivative for homocysteine remethylation to methionine. We investigated the effect of antisense-mediated inhibition of MTHFR on survival of human cancer cells. EXPERIMENTAL DESIGN: We examined the in vitro and in vivo anticancer effects of a combination of MTHFR antisense and standard cytotoxic drugs. RESULTS: Specific antisense against MTHFR (EX5) showed significant inhibitory effects on growth of human colon, lung, breast, prostate, and neuroblastoma tumor cells in vitro compared with that of the control oligonucleotide. Cytotoxic drugs (5-fluorouracil, cisplatin, or paclitaxel) potentiated the effect of EX5. In vivo, antisense alone or in combination with cytotoxic drugs inhibited the growth of human colon and lung carcinoma xenografts. In comparison with control oligonucleotide, treatment with EX5 inhibited growth of colon tumors and lung tumors by 60% and 45%, respectively. EX5 with 5-fluorouracil decreased growth of colon tumors by an additional 30% compared with EX5 alone, and EX5 with cisplatin decreased growth of lung tumors by an additional 40% compared with cisplatin alone. Growth inhibition by EX5 was associated with decreased amounts of MTHFR protein and with increased amounts of an apoptosis marker. CONCLUSIONS: Our results confirm that MTHFR inhibition decreases tumor growth and suggest that inhibition of MTHFR by antisense or small molecules may be a novel anticancer approach.


Assuntos
Neoplasias da Mama/patologia , Sobrevivência Celular , Neoplasias do Colo/patologia , Neoplasias Pulmonares/patologia , Metilenotetra-Hidrofolato Redutase (NADPH2)/antagonistas & inibidores , Metilenotetra-Hidrofolato Redutase (NADPH2)/farmacologia , Neuroblastoma/patologia , Oligonucleotídeos Antissenso/farmacologia , Neoplasias da Próstata/patologia , Antineoplásicos/farmacologia , Proliferação de Células , Cisplatino/farmacologia , Feminino , Humanos , Masculino , Células Tumorais Cultivadas
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