Much more than you expected: The non-DHFR-mediated effects of methotrexate

Šrámek, Martin; Neradil, Jakub; Veselská, Renata

doi:10.1016/j.bbagen.2016.12.014

Cited by 37 publications

(36 citation statements)

References 54 publications

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“…MTX Activity in NAMPT-Deficient Cells Is Folate Dependent. The antiproliferative activity of MTX is primarily mediated through the competitive inhibition of DHFR resulting in depletion of the intracellular pool of bioactive folates; however, folate-independent mechanisms of action have been proposed (Dolezalová et al, 2005;Funk et al, 2013;Sramek et al, 2017). The antifolate effects of MTX are reversible through supplementation with the reduced and methylated form of folate, folinic acid, also referred to as 5-formyl tetrahydrofolate (Shea et al, 2014;Koh et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

Nicotinamide Phosphoribosyltransferase Deficiency Potentiates the Antiproliferative Activity of Methotrexate through Enhanced Depletion of Intracellular ATP

Singh

Haandel

Heruth

et al. 2018

J Pharmacol Exp Ther

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Lower plasma nicotinamide phosphoribosyltransferase (NAMPT) levels are associated with improved response to methotrexate (MTX) in patients with juvenile idiopathic arthritis. Cell-based studies confirmed that reduced cellular NAMPT activity potentiates the pharmacologic activity of MTX; however, the mechanism of this interaction has yet to be defined. Therefore, in this study, we investigate the mechanism of enhanced pharmacologic activity of MTX in NAMPT-deficient A549 cells. Small interfering RNA-based silencing of NAMPT expression resulted in a greater than 3-fold increase in sensitivity to MTX ( < 0.005) that was completely reversed by supplementation with folinic acid. Despite a 68% reduction in cellular NAD levels in NAMPT-deficient cells, no change in expression or activity of dihydrofolate reductase was observed and uptake of MTX was not significantly altered. MTX did not potentiate the depletion of cellular NAD levels, but NAMPT-deficient cells had significant elevations in levels of intermediates of de novo purine biosynthesis and were 4-fold more sensitive to depletion of ATP by MTX ( < 0.005). Supplementation with hypoxanthine and thymidine completely reversed the antiproliferative activity of MTX in NAMPT-deficient cells and corresponded to repletion of the cellular ATP pool without any effect on NAD levels. Together, these findings demonstrate that increased MTX activity with decreased NAMPT expression is dependent on the antifolate activity of MTX and is driven by enhanced sensitivity to the ATP-depleting effects of MTX. For the first time, these findings provide mechanistic details to explain the increase in pharmacological activity of MTX under conditions of reduced NAMPT activity.

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Section: Resultsmentioning

confidence: 99%

Nicotinamide Phosphoribosyltransferase Deficiency Potentiates the Antiproliferative Activity of Methotrexate through Enhanced Depletion of Intracellular ATP

Singh

Haandel

Heruth

et al. 2018

J Pharmacol Exp Ther

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“…MTX shows a binding affinity to human DHFR (hDHFR) 1000-fold higher than that of folic acid [16], explaining its clinical application as anticancer, anti-inflammatory and immunosuppressive agent. Indeed, the MTX capability of affecting different intracellular pathways has been very recently described, highlighting a rather complex mechanism of action besides the most important therapeutic activity related to hDHFR inhibition [18]. Ongoing research efforts to develop novel antifolates for cancer chemotherapy and microbial infections continue to be extensively reviewed [19].…”

Section: Introductionmentioning

confidence: 99%

Host dihydrofolate reductase (DHFR)-directed cycloguanil analogues endowed with activity against influenza virus and respiratory syncytial virus

Tonelli

Naesens

Gazzarrini

et al. 2017

European Journal of Medicinal Chemistry

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We have identified a series of 1-aryl-4,6-diamino-1,2-dihydrotriazines, structurally related to the antimalarial drug cycloguanil, as new inhibitors of influenza A and B virus and respiratory syncytial virus (RSV) via targeting of the host dihydrofolate reductase (DHFR) enzyme. Most analogues proved active against influenza B virus in the low micromolar range, and the best compounds (11, 13, 14 and 16) even reached the sub-micromolar potency of zanamivir (EC = 0.060 μM), and markedly exceeded (up to 327 times) the antiviral efficacy of ribavirin. Activity was also observed for two influenza A strains, including a virus with the S31N mutant form of M2 proton channel, which is the most prevalent resistance mutation for amantadine. Importantly, the compounds displayed nanomolar activity against RSV and a superior selectivity index, since the ratio of cytotoxic to antiviral concentration was >10,000 for the three most active compounds 11, 14 and 16 (EC ∼0.008 μM), far surpassing the potency and safety profile of the licensed drug ribavirin (EC = 5.8 μM, SI > 43).

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“…The median age at diagnosis is 65 years, and an increase in the incidence of this cancer has been noted over the past few decades 2‐5 . The prevailing therapy for newly diagnosed PCNSL is methotrexate (MTX), primarily a competitive inhibitor of dihydrofolate reductase that is responsible for folate activation in the thymine and purine biosynthetic pathway 6 . Although MTX is a potent cytotoxic agent, poor blood‐brain barrier permeability necessitates administration of high‐dose methotrexate (HD‐MTX), typically 1–8 g/m 2 in combination with whole‐brain radiotherapy or other cytotoxic chemotherapy agents for treatment of PCNSL 1 .…”

mentioning

confidence: 99%

“…for newly diagnosed PCNSL is methotrexate (MTX), primarily a competitive inhibitor of dihydrofolate reductase that is responsible for folate activation in the thymine and purine biosynthetic pathway. 6 Although MTX is a potent cytotoxic agent, poor blood-brain barrier permeability necessitates administration of highdose methotrexate (HD-MTX), typically 1-8 g/ m 2 in combination with whole-brain radiotherapy or other cytotoxic chemotherapy agents for treatment of PCNSL. 1 Administration of HD-MTX to target brain cancer cells can negatively impact normal cells resulting in significant toxicities.…”

mentioning

confidence: 99%

Comparison of Body Size, Morphomics, and Kidney Function as Covariates of High‐Dose Methotrexate Clearance in Obese Adults with Primary Central Nervous System Lymphoma

et al. 2020

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Background High‐dose methotrexate (HD‐MTX) is used to treat primary central nervous system lymphoma (PCNSL), but potential differences in MTX clearance (CL) due to obesity have not been studied. We characterized the relationship between HD‐MTX CL and computed tomography (CT)‐generated body composition (morphomic), body size descriptors, and laboratory measurements in a cohort of obese and non‐obese patients with PCNSL. Methods Medical records from adult patients with PCNSL treated with HD‐MTX over a 10‐year period were queried. Individuals with CT data within 30 days of the first cycle of treatment were included. Population pharmacokinetic analysis was performed using a 2‐compartment base structural model. We specifically compared body surface area (BSA) to standard body size, morphomic, and renal function estimation methods as covariates of HD‐MTX CL. Results The final data set consisted of non‐obese (n=45) and obese (n=28) patients with 291 observations (3–7 samples per patient) with a mean (standard deviation) weight of 69.8 (11.6) kg and 104 (14.9) kg, respectively (p=0.0001). Vertebral body height was more informative than BSA of MTX CL. Similarly, a CL model incorporating age, albumin, and serum creatinine was more informative than kidney function equations and body size. The final model of MTX CL was based on age, albumin, serum creatinine, and vertebral body height. Conclusions Common clinical variables coupled with vertebral body height are more predictive of first cycle MTX CL than BSA, alternate body size descriptors, and commonly used kidney function equations.

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Much more than you expected: The non-DHFR-mediated effects of methotrexate

Cited by 37 publications

References 54 publications

Nicotinamide Phosphoribosyltransferase Deficiency Potentiates the Antiproliferative Activity of Methotrexate through Enhanced Depletion of Intracellular ATP

Nicotinamide Phosphoribosyltransferase Deficiency Potentiates the Antiproliferative Activity of Methotrexate through Enhanced Depletion of Intracellular ATP

Host dihydrofolate reductase (DHFR)-directed cycloguanil analogues endowed with activity against influenza virus and respiratory syncytial virus

Comparison of Body Size, Morphomics, and Kidney Function as Covariates of High‐Dose Methotrexate Clearance in Obese Adults with Primary Central Nervous System Lymphoma

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