Folylpoly-γ-glutamate synthetase: A key determinant of folate homeostasis and antifolate resistance in cancer

Raz, Shachar; Stark, Michal; Assaraf, Yehuda G.

doi:10.1016/j.drup.2016.06.004

Cited by 65 publications

(41 citation statements)

References 206 publications

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“…An indispensable condition for folic acid to be utilized within the remethylation pathway of Hcy is that its cellular uptake must be irreversible. The capacity of cells to accumulate folates is attributable to the activity of folypoly-γ-glutamate synthetase, an ATP dependent ligase, which catalyzes the attachment of 1-7 glutamate residues to THF, one glutamate residue after the other [18,19].…”

Section: Introductionmentioning

confidence: 99%

“…This function of Oxo provides a strong rational as the synthesis of glutamic acid results in an increase of polyglutamate-folate. This is an indispensable condition for the intracellular trapping of folic acid because the long-chain folylpolyglutamates, with long negatively charged tails, are poorly recognized by the membrane carriers responsible for efflux across the cell membrane [19].…”

Section: Introductionmentioning

confidence: 99%

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Influence of Dietary Supplementation for Hyperhomocysteinemia Treatments

Vezzoli

Dellanoce

Caimi³

et al. 2020

Nutrients

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Hyperhomocysteinemia is recognized as risk factor for cardiovascular and age-associated diseases. Folic acid supplementation efficiently lowers plasma homocysteine (Hcy) levels, but high intake may negatively affect health because of unnatural levels of unmetabolized folic acid in the systemic circulation. Oxoproline (Oxo) provides by glutamic acid production an increase of intracellular folic acid trapping. Aim of this study was to compare the efficacy of three supplementation protocols: (1) traditional therapy (5-methyl-tetrahydrofolate: 15 mg/day); (2) 5 mL/day of Oxo with 300 μg folic acid (oxifolic); (3) 5 mL/day of Oxo alone (magnesio+) in a 90 days randomized trial on thirty-two moderate hyperhomocysteinemic (18.6 ± 2.4 μmol·L−1) patients (age 48 ± 14 years). Thiols: cysteine (Cys), cysteinylglycine (Cys–Gly) and glutathione levels were assessed too. Every supplementation induced significant (p range <0.05–0.0001) reductions of Hcy level and Cys concentration after the three protocols adopted. Otherwise glutathione concentration significantly increased after oxifolic (p < 0.01) and traditional (p < 0.05) supplementation. The integration of Oxo resulted an interesting alternative to traditional therapy because absence or minimal number of folates in the integrator eliminates any chance of excess that can constitute a long-term risk.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Influence of Dietary Supplementation for Hyperhomocysteinemia Treatments

Vezzoli

Dellanoce

Caimi³

et al. 2020

Nutrients

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“…The overexpression of the detoxifying enzyme glutathione-S-transferase p1 determines resistance to cisplatin [3]. The reduced expression of the folate carrier SLC19A1 [4,5,6] or the folate metabolizing enzyme folylpoly-γ-glutamate synthetase [7] causes resistance to methotrexate. P-glycoprotein (P-gp) is the main determinant of resistance to Dox, which is actively effluxed by this plasma membrane-associated transporter [8].…”

Section: Introductionmentioning

confidence: 99%

Pleiotropic activities of nitric oxide-releasing doxorubicin on P-glycoprotein/ABCB1

Costamagna,

Kopecka,

Riganti

2020

J. Mol. Clin. Med.

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Doxorubicin is one of the first-line chemotherapeutic drugs for osteosarcoma, but the rate of success is below 60% of patients. The main cause of this low success is the presence of P-glycoprotein (P-gp/ABCB1) that effluxes the drug, limiting the intracellular accumulation and toxicity of Doxorubicin. P-gp also inhibits immunogenic cell death promoted by Doxorubicin. Nitric oxide-releasing Doxorubicin is a synthetic anthracycline effective against P-gppositive osteosarcoma cells. It is not known how it impacts on P-gp expression and immunogenic cell death induction. To address this point, we treated human Doxorubicinsensitive osteosarcoma U-2OS cells and their resistant variants with increasing amount of P-gp, with Dox and Nitric oxide-releasing Doxorubicin. While Doxorubicin was cytotoxic only in U-2OS cells, Nitric oxide-releasing Doxorubicin maintained its cytotoxic properties in all the resistant variants. Nitric oxide-releasing Doxorubicin elicited a strong nitrosative stress in whole cell extracts, endoplasmic reticulum and plasma membrane. P-gp was nitrated in all these compartments. The nitration caused protein ubiquitination and lower catalytic efficacy. The removal of P-gp from cell surface upon Nitric oxide-releasing Doxorubicin treatment disrupted its interaction with calreticulin, an immunogenic cell death-inducer that is inhibited by P-gp. Drug resistant cells treated with Nitric oxide-releasing Doxorubicin exposed calreticulin, were phagocytized by dendritic cells and expanded anti-tumor CD8 + T-lymphocytes. The efficacy of Nitric oxide-releasing Doxorubicin was validated in Dox-resistant osteosarcoma xenografts and was higher in immune-competent humanized mice than in immune-deficient mice, confirming that part of Nitric oxide-releasing Doxorubicin efficacy relies on the restoration of immunogenic cell death. Nitric oxide-releasing Doxorubicin was a pleiotropic anthracycline reducing activity and expression of P-gp, and restoring immunogenic cell death. It can be an innovative drug against P-gpexpressing/ Doxorubicin-resistant osteosarcomas.

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“…Following cellular uptake of MTX via the reduced folate carrier (RFC), one of the critical factors for the therapeutic effects of MTX involves the intracellular conversion into MTX-polyglutamates (MTX-PG n ). This process is catalyzed by the enzyme folylpolyglutamate synthetase (FPGS), which attaches multiple glutamate moieties (n = 2-5 depending on the MTX dose and duration of infusion/treatment) [5]. MTX polyglutamylation results in enhanced intracellular retention because long-chain polyanionic MTX-PG n cannot be exported from cells by ABC drug efflux transporters [6].…”

mentioning

confidence: 99%

“…Second, the impact of the FPGS activity for MTX-polyglutamylation in RA is still poorly understood. In leukemia, loss of FPGS catalytic activity along with diminished MTX-PG n accumulation in leukemic blast cells has been recognized as a common cause of non-response and poor overall survival of leukemia patients treated with high-dose MTX [5,6,23]. Recently, it was demonstrated that aberrant pre-mRNA splicing of FPGS could constitute a molecular basis for the loss of Figure 1.…”

mentioning

confidence: 99%