Determinants of Erythrocyte Methotrexate Polyglutamate Levels in Rheumatoid Arthritis

Boer, Ethan den; Rotte, Maurits C J F de; Pluijm, Saskia M F; Heil, Sandra G.; Hazes, Johanna M. W.; Jonge, Robert de

doi:10.3899/jrheum.131290

Cited by 33 publications

(23 citation statements)

References 40 publications

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“…Of note, aside from its use in cancer therapy, the antifolate MTX represents the "anchor drug" for chronic treatment of autoimmune diseases such as rheumatoid arthritis. Here, intracellular erythrocyte concentration of MTX and mean MTX plasma concentration after chronic, low-dose MTX were previously reported to be in a comparable, even slightly higher, nM range to our chosen drug concentration of 50 nM [40,41]. This implies an additional, potential significance of our findings in cancer patients that undergo chronic MTX therapy for an arthritic comorbidity and might warrant further clinical retrospective and prospective investigations beyond the scope of this study.…”

Section: Discussionsupporting

confidence: 68%

Mitochondrial One-Carbon Flux has a Growth-Independent Role in Promoting Breast Cancer Metastasis

Kiweler

Delbrouck

Neises

et al. 2021

Preprint

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Progression of primary cancer to metastatic disease is the most common cause of death in cancer patients with minimal treatment options available. Canonical drugs mainly target the proliferative capacity of cancer cells, which often leaves slow-proliferating, persistent cancer cells unaffected. Thus, we aimed to identify metabolic determinants that enable cell plasticity and foster treatment resistance and tumor escape. Using a panel of anti-cancer drugs, we uncovered that antifolates, despite inducing strong growth arrest, did not impact the cancer cell’s motility potential, indicating that nucleotide synthesis is dispensable for cell motility. Prolonged treatment even selected for more motile cancer subpopulations. We found that cytosolic inhibition of DHFR by MTX only abrogates cytosolic folate cycle, while mitochondrial one-carbon cycle remains highly active. Despite a decreased cellular demand for biomass production, de novo serine synthesis and formate overflow are increased, suggesting that mitochondria provide a protective environment that allows serine catabolism to support cellular motility during nucleotide synthesis inhibition. Enhanced motility of growth-arrested cells was reduced by inhibition of PHGDH-dependent de novo serine synthesis and genetic silencing of mitochondrial one-carbon cycle. In vivo targeting of mitochondrial one-carbon cycle and formate overflow strongly and significantly reduced lung metastasis formation in an orthotopic breast cancer model. In summary, we identified mitochondrial serine catabolism as a targetable, growth-independent metabolic vulnerability to limit metastatic progression.

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Section: Discussionsupporting

confidence: 68%

Mitochondrial One-Carbon Flux has a Growth-Independent Role in Promoting Breast Cancer Metastasis

Kiweler

Delbrouck

Neises

et al. 2021

Preprint

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“…Some studies have suggested measuring intracellular methotrexate polyglutamates as a biomarker, but cost and lack of wide availability have been barriers for routine use. 15,16…”

Section: Introductionmentioning

confidence: 99%

Reduction in Serum Uric Acid may be Related to Methotrexate Efficacy in Early Rheumatoid Arthritis: Data from the Canadian Early Arthritis Cohort (CATCH)

Lee

Bykerk

Boire

et al. 2016

Clin Med�Insights�Arthritis�Musculoskelet Disord

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OBJECTIVESThe mechanism of action of methotrexate in rheumatoid arthritis (RA) is complex. It may increase adenosine levels by blocking its conversion to uric acid (UA). This study was done to determine if methotrexate lowers UA in early RA (ERA).METHODSData were obtained from Canadian Early Arthritis Cohort, an incident ERA cohort. All ERA patients with serial UA measurements were included, comparing those with methotrexate use vs. no methotrexate exposure (controls). Analyses were exploratory. Patients with concomitant gout or taking UA-lowering therapies were excluded.RESULTSIn total, 49 of the 2,524 ERA patients were identified with data available for both pre-methotrexate UA levels and post-methotrexate UA levels (300 µmol/L and 273 µmol/L, respectively; P = 0.035). The control group not taking methotrexate had a mean baseline UA level of 280 µmol/L and a follow-up level of 282 µmol/L (P = 0.448); mean change in UA with methotrexate was −26.8 µmol/L vs. 2.3 µmol/L in the no methotrexate group (P = 0.042). Methotrexate users with a decrease in UA had a disease activity score of 2.37 for 28 joints when compared with the controls (3.26) at 18 months (P = 0.042). Methotrexate users with decreased UA had a lower swollen joint count (SJC) of 0.9 at 18 months, whereas methotrexate users without lowering of UA had an SJC of 4.5 (P = 0.035). Other analyses were not significant.CONCLUSIONSMethotrexate response is associated with lowering of serum UA in ERA compared to nonusers. This may be due to changes in adenosine levels. Methotrexate response is associated with lower UA and fewer swollen joints compared to nonresponders.

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“…5-fluorouracil), target folate-mediated one-carbon metabolism (Chon et al, 2017;Yu et al, 2018). Toxicity as well as efficiency of these drugs have been linked to folate status of the patients (den Boer et al, 2014;den Hoed et al, 2015;Verhoef et al, 2017;Yan et al, 2016). The folate biosynthesis capacity may as such have important implications for treatment outcomes, since folate levels in the circulation as well as the target tissue (e.g.…”

Section: Discussionmentioning

confidence: 99%

Bacterial folate biosynthesis and colorectal cancer risk: more than just a gut feeling

Kok

Steegenga

Smid

et al. 2018

Critical Reviews in Food Science and Nutrition

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Folate is a B-vitamin with an important role in health and disease. The optimal folate status with regard to human health remains controversial. A low intake of natural folate as well as excessive intake of synthetic folic acid, were previously linked to an increased risk of colorectal cancer or with aberrant molecular pathways related to carcinogenesis in some studies. Importantly, most studies conducted so far, solely focused on dietary intake or circulating levels of folate in relation to cancer risk. Notably, diet or dietary supplements are not the only sources of folate. Several bacteria in the gastrointestinal tract can synthesize B-vitamins, including folate, in quantities that resemble dietary intake. The impact of bacterial folate biosynthesis concerning human health and disease remains unexplored. This review highlights current insights into folate biosynthesis by intestinal bacteria and its implications for processes relevant to cancer development, such as epigenetic DNA modifications and DNA synthesis. Moreover, we will reflect on the emerging question whether food-grade or intestinal bacteria can be considered a potential target to ensure sufficient levels of folate in the gastrointestinal tract and, hence the relevance of bacterial folate biosynthesis for disease prevention or treatment.

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Determinants of Erythrocyte Methotrexate Polyglutamate Levels in Rheumatoid Arthritis

Cited by 33 publications

References 40 publications

Mitochondrial One-Carbon Flux has a Growth-Independent Role in Promoting Breast Cancer Metastasis

Mitochondrial One-Carbon Flux has a Growth-Independent Role in Promoting Breast Cancer Metastasis

Reduction in Serum Uric Acid may be Related to Methotrexate Efficacy in Early Rheumatoid Arthritis: Data from the Canadian Early Arthritis Cohort (CATCH)

Bacterial folate biosynthesis and colorectal cancer risk: more than just a gut feeling

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