Gene/Protein
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Symptom
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Enzyme
Compound
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Target Concepts:
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Query: EC:1.5.1.3 (
dihydrofolate reductase
)
5,819
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Antifolates exert their antiproliferative activity through the inhibition of
dihydrofolate reductase
and, as a consequence, of thymidylate synthesis, thereby inducing nucleotide misincorporation and impairment of DNA synthesis. We investigated the processes involved in the repair of antifolate-induced damage and their relationship with cell death. Since misincorporated bases may be removed by DNA mismatch repair (MMR), the study was carried out on the MMR-proficient human cell lines HeLa and HCT116+chr3, and, in parallel, on the MMR-deficient cell lines HeLa cell-clone12, defective in the protein hPMS2, and HCT116, with an inactive hMLH1. After treatment with methotrexate (MTX), we observed that DNA repair synthesis occurs independently of the cellular MMR function. Clear signs of apoptosis such as nuclear shrinkage, chromatin condensation and degradation, DNA laddering, and poly (ADP-ribose) polymerase (
PARP
) proteolysis, were visible in both MMR(+) and MMR(-) cells. Remarkably, cell viability was lower and the apoptotic process was triggered more efficiently in the MMR-competent cells.
...
PMID:Different effects of methotrexate on DNA mismatch repair proficient and deficient cells. 1137 49
alpha-Hydroxy-9-cis-octadecenoic acid, a synthetic fatty acid that modifies the composition and structure of lipid membranes. 2-Hydroxyoleic acid (HOA) generated interest due to its potent, yet nontoxic, anticancer activity. It induces cell cycle arrest in human lung cancer (A549) cells and apoptosis in human leukemia (Jurkat) cells. These two pathways may explain how HOA induces regression of a variety of cancers. We showed that HOA repressed the expression of
dihydrofolate reductase
(
DHFR
), the enzyme responsible for tetrahydrofolate (THF) synthesis. Folinic acid, which readily produces THF without the participation of
DHFR
, reverses the antitumor effects of HOA in A549 and Jurkat cells, as well as the inhibitory influence on cyclin D and cdk2 in A549 cells, and on DNA and
PARP
degradation in Jurkat cells. This effect was very specific, because either elaidic acid (an analog of HOA) or other lipids, failed to alter A549 or Jurkat cell growth. THF is a cofactor necessary for DNA synthesis. Thus, impairment of DNA synthesis appears to be a common mechanism involved in the different responses elicited by cancer cells following treatment with HOA, namely cell cycle arrest or apoptosis. Compared with other antifolates, such as methotrexate, HOA did not directly inhibit
DHFR
but rather, it repressed its expression, a mode of action that offers certain therapeutic advantages. These results not only demonstrate the effect of a fatty acid on the expression of
DHFR
, but also emphasize the potential of HOA to be used as a wide-spectrum drug against cancer.
...
PMID:Pivotal role of dihydrofolate reductase knockdown in the anticancer activity of 2-hydroxyoleic acid. 1966 84
In view of the mandate from the World Health Organization (WHO) for developing novel drug candidates against human lymphatic filariasis,
dihydrofolate reductase
(
DHFR
) inhibitors are explored as potential antifilarial agents. The in vitro biological evaluation of an in-house library of 12 diverse antifolate compounds with 2,4-diaminopyrimidine and 2,4-diamino-s-triazine structural features against Brugia malayi is reported. To confirm the
DHFR
inhibitory potential of these compounds, reversal studies using folic acid and folinic acid were undertaken. Inhibition of
DHFR
can induce apoptosis; in this light, preliminary evidence of apoptosis by test compounds was detected using ethidium bromide-acridine orange staining and the poly(adenosine diphosphate-ribose) polymerase (
PARP
) inhibition assay. Among the evaluated compounds, 3 showed significant activity against both microfilariae and adult worms. The effects of 2 of these compounds were mostly reversed by folic acid, validating
DHFR
inhibitory activity. Partial reversal of the effect of 2 compounds by folinic acid and non-reversal of the effect of the third compound both by folic and folinic acids are discussed. This study opens new avenues for the discovery of lead molecules by exploiting the folate pathway against one of the major neglected tropical diseases, filariasis.
...
PMID:Exploration of 2, 4-diaminopyrimidine and 2, 4-diamino-s-triazine derivatives as potential antifilarial agents. 2355 64
GMX1778 and its prodrug GMX1777 represent a new class of cancer drugs that targets nicotinamide phosphoribosyltransferase (NAMPT) as a new strategy to interfere with biosynthesis of the key enzymatic cofactor NAD, which is critical for a number of cell functions, including DNA repair. Using a genome-wide synthetic lethal siRNA screen, we identified the folate pathway-related genes, deoxyuridine triphosphatase and
dihydrofolate reductase
, the silencing of which sensitized non-small cell lung carcinoma (NSCLC) cells to the cytotoxic effects of GMX. Pemetrexed is an inhibitor of
dihydrofolate reductase
currently used to treat patients with nonsquamous NSCLC. We found that combining pemetrexed with GMX1777 produced a synergistic therapeutic benefit in A549 and H1299 NSCLC cells in vitro and in a mouse A549 xenograft model of lung cancer. Pemetrexed is known to activate PARPs, thereby accelerating NAD consumption. Genetic or pharmacologic blockade of
PARP
activity inhibited this effect, impairing cell death by pemetrexed either alone or in combination with GMX1777. Conversely, inhibiting the base excision repair pathway accentuated NAD decline in response to GMX and the cytotoxicity of both agents either alone or in combination. These findings provide a mechanistic rationale for combining GMX1777 with pemetrexed as an effective new therapeutic strategy to treat nonsquamous NSCLC.
...
PMID:Synergy between the NAMPT inhibitor GMX1777(8) and pemetrexed in non-small cell lung cancer cells is mediated by PARP activation and enhanced NAD consumption. 2514 69
Methotrexate (MTX) is a folic acid antagonist and widely used for acute lymphoblastic leukemia (ALL) in children. MTX is associated with acute and chronic neurotoxicity during treatment, however the underlying mechanism is still poorly understood. In this study we investigate whether MTX is neurovirulent to astrocytes in the Central Nervous System (CNS) of adolescent mice. We demonstrated that MTX induced severe cytotoxicity in C6 astrocyte-like cell line and rat primary cultures of astrocytes in a dose-dependent manner. Moreover, GFAP-labeled astrocyte cells significantly decreased in the mouse spinal cord and brain. Furthermore, protein levels of
PARP
and pro-Caspase-3 were reduced by MTX, indicating MTX-induced apoptosis leads to the astrocytes loss. Notably, overexpression of
dihydrofolate reductase
(
DHFR
) or exogenous addition of folate markedly reversed the astrocytes toxicity induced by MTX through activating folate metabolism pathway. Taken together, our study provides evidence for neurotoxic effect of MTX-induced astrocytes apoptosis both in vitro and in vivo with disruption of folate metabolism, and additional supplement of folate may provide novel approaches for alleviating the astrocytes toxicity induced by MTX in the clinic.
...
PMID:Methotrexate induces astrocyte apoptosis by disrupting folate metabolism in the mouse juvenile central nervous system. 3050 84
