Molecular toxicity of methotrexate in rheumatoid arthritis treatment: A novel perspective and therapeutic implications

Katturajan, Ramkumar; Vijayalakshmi, S.; Rasool, Mahaboobkhan; Sabina, Evan Prince

doi:10.1016/j.tox.2021.152909

Cited by 33 publications

(19 citation statements)

References 70 publications

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“…24 In our study, the folate pathway was not significantly altered in metabolomic profiles for patients with delayed excretion of MTX, which may be explained by the fact that leucovorin partially restored the folate pool. 25 Interestingly, the folic acid pathway will indirectly affect the methionine and adenosine pathways, resulting in higher homocysteine levels and intracellular oxidative stress, 26 which is in…”

Section: Discussionmentioning

confidence: 99%

Metabolomic profiling reveals the mechanisms underlying the nephrotoxicity of methotrexate in children with acute lymphoblastic leukemia

Cheng

Chen

Zhao

et al. 2023

Pediatric Blood & Cancer

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BackgroundMethotrexate is widely recommended as a first‐line treatment for the intensive systemic and consolidation phases of childhood acute lymphoblastic leukemia. However, methotrexate‐induced nephrotoxicity is a severe adverse reaction, of which the mechanisms remain unclear.MethodsAn untargeted metabolomics analysis of serum from childhood acute lymphoblastic leukemia patients with delayed methotrexate excretion, with or without acute kidney injury, was performed to identify altered metabolites and metabolic pathways. An independent external validation cohort and in vitro HK‐2 cell assays further verified the candidate metabolites, and explored the mechanisms underlying the nephrotoxicity of methotrexate.ResultsFour metabolites showed significant differences between normal excretion and delayed excretion, seven metabolites reflected the differences between groups with or without acute kidney injury, and six pathways were finally enriched. In particular, oxidized glutathione was confirmed as a candidate metabolite involved in the toxicity of methotrexate. We further explored the role of glutathione deprivation‐induced ferroptosis on methotrexate cytotoxicity, and it was found that methotrexate overload significantly reduced cell viability, triggered reactive oxygen species and intracellular Fe2+ accumulation, and altered the expression of ferroptosis‐related proteins in HK‐2 cells. These methotrexate‐induced changes were alleviated or reversed by the administration of a ferroptosis inhibitor, further suggesting that ferroptosis promoted methotrexate‐induced cytotoxicity in HK‐2 cells.ConclusionsOur findings revealed complex metabolomic profiles and provided novel insights into the mechanism by which ferroptosis contributes to the nephrotoxic effects of methotrexate.

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Section: Discussionmentioning

confidence: 99%

Metabolomic profiling reveals the mechanisms underlying the nephrotoxicity of methotrexate in children with acute lymphoblastic leukemia

Cheng

Chen

Zhao

et al. 2023

Pediatric Blood & Cancer

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“…MTX is an antimetabolite therapeutics that is extensively used as an anticancer and immune-suppressive drug, although its therapeutic e cacy is hampered by organ toxicities (19). One of the most dangerous side effects of long-term MTX treatment is hepatotoxicity, which is caused by the accumulation of 7hydroxymethotrexate, the drug's primary metabolite (20).…”

Section: Discussionmentioning

confidence: 99%

Hepatoprotective effect of morin against methotrexate-induced hepatotoxicity via targeting Nrf2/HO-1 and Bax/Bcl2/Caspase-3 signaling pathways

Kızıl

Çağlayan

Darendelioğlu

et al. 2022

Preprint

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Background Organ toxicity limits the therapeutic efficacy of methotrexate (MTX), an anti-metabolite therapeutic that is frequently used as an anti-cancer and immunosuppressive medicine. Hepatocellular toxicity is among the most severe side effects of long-term MTX use. The present study unveils new confirmations as regards the remedial effects of morin on MTX-induced hepatocellular injury through regulation of oxidative stress, apoptosis and MAPK signaling. Methods Rats were subjected to oral treatment of morin (50 and 100 mg/kg body weight) for 10 days. Hepatotoxicity was induced by single intraperitoneal injection of MTX (20 mg/kg body weight) on the 5th day. Results MTX related hepatic injury was associated with increased MDA while decreased GSH levels, the activities of endogen antioxidants (glutathione peroxidase, superoxide dismutase and catalase) and mRNA levels of HO-1 and Nrf2 in the hepatic tissue. MTX treatment also resulted in apoptosis in the liver tissue via increasing mRNA transcript levels of Bax, caspase-3, Apaf-1 and downregulation of Bcl-2. Conversely, treatment with morin at different doses (50 and 100 mg/kg) considerably mitigated MTX-induced oxidative stress and apoptosis in the liver tissue. Morin also mitigated MTX-induced increases of ALT, ALP and AST levels, downregulated mRNA expressions of matrix metalloproteinases (MMP-2 and MMP-9), MAPK14 and MAPK15, JNK, Akt2 and FOXO1 genes. Conclusions According to the findings of this study, morin may be a potential way to shield the liver tissue from the oxidative damage and apoptosis.

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“…Methotrexate (MTX), an efficacious DMARDs, is the first line for the treatment of RA. However, some adverse effects of MTX have limited their extensive clinical application, such as liver dysfunction, renal failure and nausea ( Katturajan et al, 2021 ). In order to overcome the disadvantages and further improve the effective in treatment, it is necessary to explore combination therapy of compounds from EH and DMARDs for the treatment of RA.…”

Section: Alternative Strategies For the Treatment Of Ramentioning

confidence: 99%

Epimedii Herba: An ancient Chinese herbal medicine in the prevention and treatment of rheumatoid arthritis

Liu-bo

Yan

et al. 2022

Front. Chem.

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Rheumatoid arthritis (RA) is a chronic, progressive inflammatory and systemic autoimmune disease resulting in severe joint destruction, lifelong suffering and considerable disability. Diverse prescriptions of traditional Chinese medicine (TCM) containing Epimedii Herba (EH) achieve greatly curative effects against RA. The present review aims to systemically summarize the therapeutic effect, pharmacological mechanism, bioavailability and safety assessment of EH to provide a novel insight for subsequent studies. The search terms included were “Epimedii Herba”, “yinyanghuo”, “arthritis, rheumatoid” and “Rheumatoid Arthritis”, and relevant literatures were collected on the database such as Google Scholar, Pubmed, Web of Science and CNKI. In this review, 15 compounds from EH for the treatment of RA were summarized from the aspects of anti-inflammatory, immunoregulatory, cartilage and bone protective, antiangiogenic and antioxidant activities. Although EH has been frequently used to treat RA in clinical practice, studies on mechanisms of these activities are still scarce. Various compounds of EH have the multifunctional traits in the treatment of RA, so EH may be a great complementary medicine option and it is necessary to pay more attention to further research and development.

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Molecular toxicity of methotrexate in rheumatoid arthritis treatment: A novel perspective and therapeutic implications

Cited by 33 publications

References 70 publications

Metabolomic profiling reveals the mechanisms underlying the nephrotoxicity of methotrexate in children with acute lymphoblastic leukemia

Metabolomic profiling reveals the mechanisms underlying the nephrotoxicity of methotrexate in children with acute lymphoblastic leukemia

Hepatoprotective effect of morin against methotrexate-induced hepatotoxicity via targeting Nrf2/HO-1 and Bax/Bcl2/Caspase-3 signaling pathways

Epimedii Herba: An ancient Chinese herbal medicine in the prevention and treatment of rheumatoid arthritis

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