Hyperproliferation of homocysteinetreated colon cancer cells is reversed by folate and 5-methyltetrahydrofolate

Akoglu, Bora; Milovic, Vladan; Caspary, W. F.; Faust, Dominik

doi:10.1007/s00394-004-0446-6

Cited by 27 publications

(20 citation statements)

References 24 publications

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“…16 Homocysteine accumulation may represent another potential mechanism for explaining gastric cancer risk in MTHFR677T carriers. 38,39 In these subjects, low MTHFR enzyme activity with reduced remethylation of homocysteine to methionine induces excessive homocysteine serum levels, which showed tumor cell growth-promoting activity in experimental models. 38,39 In conclusion, the role of MTHFR677C/T polymorphism in gastric cancer susceptibility is a promising field of investigation.…”

Section: Discussionmentioning

confidence: 99%

“…38,39 In these subjects, low MTHFR enzyme activity with reduced remethylation of homocysteine to methionine induces excessive homocysteine serum levels, which showed tumor cell growth-promoting activity in experimental models. 38,39 In conclusion, the role of MTHFR677C/T polymorphism in gastric cancer susceptibility is a promising field of investigation. Regardless of ethnicity, the MTHFR677T allele appears to be associated with gastric cancer risk, and additional studies are warranted given the opportunity of preventive nutritional interventions 40 and screening programs in at-risk individuals.…”

Section: Discussionmentioning

confidence: 99%

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Methylenetetrahydrofolate reductase 677C/T gene polymorphism, gastric cancer susceptibility and genomic DNA hypomethylation in an at‐risk Italian population

Graziano

Kawakami

Ruzzo

et al. 2005

Intl Journal of Cancer

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We performed a case-control study to examine the relationship between MTHFR C677T gene polymorphism (MTHFR677C/T) and gastric cancer susceptibility in at-risk populations in central Italy. To explore genomic DNA hypomethylation as a potential etiologic mechanism, this phenomenon was evaluated in carriers of the MTHFR677T/T genotype and carriers of the wild-type MTHFR677C/C genotype. Lymphocyte genomic DNA from 162 gastric cancer patients and 164 controls was used for MTHFR677C/T genotyping. Unconditional regression analysis with ORs and 95% CIs was used to investigate the association of the polymorphism with disease. Genomic DNA methylation status by an established enzymatic assay that measures the DNA accepting capacity of methyl groups (inversely related to endogenous methylation) was assessed in a random sample of 40 carriers of the wild-type MTHFR677C/C genotype and 40 carriers of the MTHFR677T/T genotype. The global allelic distribution was in Hardy-Weinberg equilibrium. The MTHFR677T allele was significantly associated with gastric cancer risk with an OR of 2.49 (95% CI 1.48-4.20) in heterozygous MTHFR677C/T carriers and an OR of 2.85 (95% CI 1.52-5.35) in homozygous MTHFR677T/T carriers. This risk association was retained in subgroup analyses by tumor histotype and location. Genomic DNA hypomethylation status in MTHFR677T/T carriers was significantly higher than in subjects with wild-type MTHF677C/C genotype (p 5 0.012). In the studied population, MTHFR677T played the role of a moderatepenetrance gastric cancer susceptibility allele. Possession of the MTHFR677T/T genotype was significantly associated with genomic DNA hypomethylation. These findings deserve further investigation in the context of novel strategies for gastric cancer prevention. ' 2005 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Methylenetetrahydrofolate reductase 677C/T gene polymorphism, gastric cancer susceptibility and genomic DNA hypomethylation in an at‐risk Italian population

Graziano

Kawakami

Ruzzo

et al. 2005

Intl Journal of Cancer

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“…Genetic defects in methionine metabolism related to methionine synthase, N 5,10 -methylenetetrahyrdofolate, also result in neural dysfunction, mental retardation, and pregnancy complications (6)(7)(8). Recent studies have linked homocysteine, folate, and DNA methylation with gastrointestinal diseases, namely inflammatory bowel disease and colon cancer (9)(10)(11)(12)(13). The underlying mechanism linking homocysteine to inflammatory disease may be the induction of leukocyte adhesion molecules and proinflammatory cytokines in vascular endothelial cells (10).…”

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confidence: 99%

Methionine transmethylation and transsulfuration in the piglet gastrointestinal tract

Riedijk

Stoll

Chacko

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

124

102

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Methionine is an indispensable sulfur amino acid that functions as a key precursor for the synthesis of homocysteine and cysteine. Studies in adult humans suggest that splanchnic tissues convert dietary methionine to homocysteine and cysteine by means of transmethylation and transsulfuration, respectively. Studies in piglets show that significant metabolism of dietary indispensable amino acids occurs in the gastrointestinal tissues (GIT), yet the metabolic fate of methionine in GIT is unknown. We show here that 20% of the dietary methionine intake is metabolized by the GIT in piglets implanted with portal and arterial catheters and fed milk formula. Based on analyses from intraduodenal and intravenous infusions of [1-13 C]methionine and [ 2 H3]methionine, we found that the whole-body methionine transmethylation and remethylation rates were significantly higher during duodenal than intravenous tracer infusion. First-pass splanchnic metabolism accounted for 18% and 43% of the whole-body transmethylation and remethylation, respectively. Significant transmethylation and transsulfuration was demonstrated in the GIT, representing Ϸ27% and Ϸ23% of whole-body fluxes, respectively. The methionine used by the GIT was metabolized into homocysteine (31%), CO 2 (40%), or tissue protein (29%). Cystathionine ␤-synthase mRNA and activity was present in multiple GITs, including intestinal epithelial cells, but was significantly lower than liver. We conclude that the GIT consumes 20% of the dietary methionine and is a significant site of net homocysteine production. Moreover, the GITs represent a significant site of whole-body transmethylation and transsulfuration, and these two pathways account for a majority of methionine used by the GITs.cystathionine ␤-synthase ͉ homocysteine ͉ intestine

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“…Elevated concentrations of plasma HCY are related to cardiovascular diseases and to cerebrovascular diseases like vascular dementia and mental cognitive dysfunction (Miller et al, 1994;Fassbender et al, 1999;Schachinger et al, 1999;Duthie et al, 2002). High HCY levels have recently been implicated as a risk factor for cancer and might be considered as a new tumor marker (Wu and Wu, 2002) and a pro-proliferative metabolite in vitro (Akoglu et al, 2004). Liver transplant recipients have increased HCY levels, probably due to the immunosuppressive therapy, in particular to the use of calcineurin inhibitors cyclosporine A (CyA) and tacrolimus (Tacrolimus).…”

Section: Introductionmentioning

confidence: 99%

The folic acid metabolite L-5-methyltetrahydrofolate effectively reduces total serum homocysteine level in orthotopic liver transplant recipients: a double-blind placebo-controlled study

Akoglu

Schrott²,

Bolouri

et al. 2007

Eur J Clin Nutr

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Objective: Hyperhomocysteinemia is a described risk factor of cardiovascular diseases. The aim of this study was the treatment of hyperhomocysteinemia in liver transplant recipients with L-5-methyltetrahydrofolate (L-5-MTHF; 1 mg) vs folic acid (1 mg) vs placebo in a double-blind placebo-controlled study and to compare the relative responsiveness of these patients to L-5-MTHF and folic acid. Subjects/Methods: Patients were recruited from Hepatology-Transplantation-Unit at Johann Wolfgang Goethe-University, Frankfurt. Sixty patients were included in this study and 12 patients dropped out for different reasons. The patients were treated over 8 weeks with supplemental L-5-MTHF or folic acid or placebo. Serum homocysteine (HCY) was analyzed with highperformance liquid chromatography (HPLC) beside routine lab tests. Results: We observed only a significant decrease of total serum HCY in the L-5-MTHF group during the study period (at week 0: 1577.7 mM; after 8 weeks treatment: 9.4172.6 mM, Po0.001). There was no significant decrease of total serum HCY neither in the folic acid group nor in the placebo group. Conclusion: The effects of L-5-MTHF are significantly more potent than folic acid itself. Therefore, lowering serum HCY in liver transplant recipients is effective with L-5-MTHF.

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Hyperproliferation of homocysteinetreated colon cancer cells is reversed by folate and 5-methyltetrahydrofolate

Abstract: Our data suggest that 5-MTHF, being the key metabolite in both the folate and homocysteine metabolic pathway, is the main modulator of growth-promoting actions of homocysteine as well as antiproliferative effects of folate in colon cancer cells.

Cited by 27 publications

References 24 publications

Methylenetetrahydrofolate reductase 677C/T gene polymorphism, gastric cancer susceptibility and genomic DNA hypomethylation in an at‐risk Italian population

Methylenetetrahydrofolate reductase 677C/T gene polymorphism, gastric cancer susceptibility and genomic DNA hypomethylation in an at‐risk Italian population

Methionine transmethylation and transsulfuration in the piglet gastrointestinal tract

The folic acid metabolite L-5-methyltetrahydrofolate effectively reduces total serum homocysteine level in orthotopic liver transplant recipients: a double-blind placebo-controlled study

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