Chapter 9 Regulation of Human Dihydrofolate Reductase Activity and Expression

Abali, Emine Ercikan; Skacel, Nancy; Celikkaya, Hilal; Hsieh, Yi-Ching

doi:10.1016/s0083-6729(08)00409-3

Cited by 48 publications

(44 citation statements)

References 88 publications

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“…The interconversion between the second ensemble and the third is slower in human DHFR than in E. coli or L. casei DHFR. It is possible that NADPS, by lowering NADPH levels, may be interfering with the interconversion of the second ensemble to third ensemble, which is the native state (Abali et al, 2008). Our results support this hypothesis, because synergy in combination studies was obtained only if the cells were treated with NADPS analogs first.…”

Section: Discussionsupporting

confidence: 77%

“…DHFR activity has been shown to increase during S-phase, because it is required for DNA synthesis (Abali et al, 2008). Because MTX blocks DNA synthesis and arrests cell growth in early S phase, we reasoned that the decrease in DHFR caused by NADPS might also block cells at the G 1 /S phase.…”

Section: The Effect Of Nadps On Dhfr Transcriptionmentioning

confidence: 99%

“…They comprise a long channel in the active site of the enzyme, positioning the 2 ligands in close proximity to enable hydride transfer from NADPH to FH 2 , generating FH 4 . Tetrahydrofolate is converted to 10-formyl and 5-10 methylene FH 4 , essential cofactors in the synthesis of purines, thymidylate, and certain amino acids (Abali et al, 2008). Inhibition of DHFR results in a depletion of the reduced folate pool, inhibition of RNA and DNA synthesis, and cell death.…”

Section: Introductionmentioning

confidence: 99%

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Enhanced Degradation of Dihydrofolate Reductase through Inhibition of NAD Kinase by Nicotinamide Analogs

Hsieh

Tedeschi²,

Lawal³

et al. 2012

Mol Pharmacol

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Dihydrofolate reductase (DHFR), because of its essential role in DNA synthesis, has been targeted for the treatment of a wide variety of human diseases, including cancer, autoimmune diseases, and infectious diseases. Methotrexate (MTX), a tight binding inhibitor of DHFR, is one of the most widely used drugs in cancer treatment and is especially effective in the treatment of acute lymphocytic leukemia, non-Hodgkin's lymphoma, and osteosarcoma. Limitations to its use in cancer include natural resistance and acquired resistance due to decreased cellular uptake and decreased retention due to impaired polyglutamylate formation and toxicity at higher doses. Here, we describe a novel mechanism to induce DHFR degradation through cofactor depletion in neoplastic cells by inhibition of NAD kinase, the only enzyme responsible for generating NADP, which is rapidly converted to NADPH by dehydrogenases/reductases. We identified an inhibitor of NAD kinase, thionicotinamide adenine dinucleotide phosphate (NADPS), which led to accelerated degradation of DHFR and to inhibition of cancer cell growth. Of importance, combination treatment of NADPS with MTX displayed significant synergy in a metastatic colon cancer cell line and was effective in a MTX-transport resistant leukemic cell line. We suggest that NAD kinase is a valid target for further inhibitor development for cancer treatment.

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Section: Discussionsupporting

confidence: 77%

Section: The Effect Of Nadps On Dhfr Transcriptionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Enhanced Degradation of Dihydrofolate Reductase through Inhibition of NAD Kinase by Nicotinamide Analogs

Hsieh

Tedeschi²,

Lawal³

et al. 2012

Mol Pharmacol

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“…In addition, over-expression of DHFR protein is observed in methotrexate-resistant cells (Assaraf, 2007). DHFR expression is regulated by multiple mechanisms (Abali et al, 2008), including gene amplification (Alt et al, 1978;Dolnick et al, 1979), Sp1 and E2F1-mediated transcriptional regulation (Dynan et al, 1986;Slansky et al, 1993), and miRNA-mediated post-transcriptional regulation (Mishra et al, 2007;Song et al, 2008;Song et al, 2010). This study, it was sought to investigate a possibility that RNA editing might also underlie as the regulation mechanism.…”

Section: Introductionmentioning

confidence: 99%

A-to-I RNA Editing Up-regulates Human Dihydrofolate Reductase in Breast Cancer

Nakano¹,

Fukami

Gotoh

et al. 2017

Journal of Biological Chemistry

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“…Tetrahydrofolate and its one carbon adducts are required for de novo synthesis of purines and thymidylate, as well as some amino acids. DHFR inhibition causes disruption of purine and thymidylate biosynthesis and DNA replication, leading to cell death [4]. Therefore, DHFR has been an attractive target for chemotherapy of many diseases including cancer [5], malaria [6], leishmania and trypanosomiasis [7] and D DAVID PUBLISHING bacterial infections [8].…”

mentioning

confidence: 99%

Anticancer and Antifolate Activities of Extracts of Six Saudi Arabian Wild Plants Used in Folk Medicine

Albalawi¹,

Bashir²,

Tawfik³

2015

JLS

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Six indigenous folk medicinal plants growing wild in the area of Tabuk, Saudi Arabia which were selected for the study of their phytochemistry as well as their biological activities as antitumor and antifolate agents. Antitumor activities of methanol extracts of the six plants were measured in vitro using three human tumor cell lines (breast, lung and CNS cancers) while antifolate activities were assessed using commercial dihyrofolate reductase obtained from Sigma Co. Among the six plant extracts tested, the most remarkable were those of Caralluma sinaica and Fagonia tenuifolia. Caralluma extract showed strong antitumor activity (low GI 50 ) against the three human tumor cell lines. Fagonia extract, on the other hand, was quite inhibitory to the growth of CNS cancer and breast cancer cell lines but much less so against lung cancer cells. Extracts of both Sonchus oleraceus and Caralluma sinaica were strongly inhibitory to DHFR. These results suggest that the mechanism of anticancer activity of Caralluma plant is through DHFR inhibition but that of Fagonia may follow a different path.

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Chapter 9 Regulation of Human Dihydrofolate Reductase Activity and Expression

Cited by 48 publications

References 88 publications

Enhanced Degradation of Dihydrofolate Reductase through Inhibition of NAD Kinase by Nicotinamide Analogs

Enhanced Degradation of Dihydrofolate Reductase through Inhibition of NAD Kinase by Nicotinamide Analogs

A-to-I RNA Editing Up-regulates Human Dihydrofolate Reductase in Breast Cancer

Anticancer and Antifolate Activities of Extracts of Six Saudi Arabian Wild Plants Used in Folk Medicine

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