The effects of drug transporters on the efficacy of methotrexate in the treatment of rheumatoid arthritis

Gao, Jinzhang; Wang, Chun; Wei, Wei

doi:10.1016/j.lfs.2020.118907

Cited by 17 publications

(8 citation statements)

References 125 publications

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“…Moreover, ABCG2 contributed to MTX resistance in RA. 35 , 36 The alleviation of the pathological phenotype of RA‐FLS and the enhanced anti‐RA effect of MTX induced by OS suggested that OS could effectively delay RA progression.…”

Section: Discussionmentioning

confidence: 99%

Osthole regulates N6‐methyladenosine‐modified TGM2 to inhibit the progression of rheumatoid arthritis and associated interstitial lung disease

Lin

Chen

Tao

et al. 2023

MedComm

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Rheumatoid arthritis (RA) is an inflammatory autoimmune disease, and RA interstitial lung disease (ILD) is a severe complication of RA. This investigation aims to determine the effect and underlying mechanism of osthole (OS), which could be extracted from Cnidium , Angelica , and Citrus plants and evaluate the role of transglutaminase 2 (TGM2) in RA and RA‐ILD. In this work, OS downregulated TGM2 to exert its additive effect with methotrexate and suppress the proliferation, migration, and invasion of RA‐fibroblast‐like synoviocytes (FLS) by attenuating NF‐κB signaling, resulting in the suppression of RA progression. Interestingly, WTAP‐mediated N6‐methyladenosine modification of TGM2 and Myc‐mediated WTAP transcription cooperatively contributed to the formation of a TGM2/Myc/WTAP‐positive feedback loop through upregulating NF‐κB signaling. Moreover, OS could downregulate the activation of the TGM2/Myc/WTAP‐positive feedback circuit. Furthermore, OS restrained the proliferation and polarization of M2 macrophages to inhibit the aggregation of lung interstitial CD11b + macrophages, and the effectiveness and non‐toxicity of OS in suppressing RA and RA‐ILD progression were verified in vivo. Finally, bioinformatics analyses validated the importance and the clinical significance of the OS‐regulated molecular network. Taken together, our work emphasized OS as an effective drug candidate and TGM2 as a promising target for RA and RA‐ILD treatment.

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Section: Discussionmentioning

confidence: 99%

Osthole regulates N6‐methyladenosine‐modified TGM2 to inhibit the progression of rheumatoid arthritis and associated interstitial lung disease

Lin

Chen

Tao

et al. 2023

MedComm

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“…Polymorphisms affecting P-glycoprotein function or expression can alter drug effect and toxicity. Possible identification of allelic variants that modulate the pharmacokinetics of a drug, allows better therapy adjustment and increases its effectiveness and safety [6] . The CC genotype of C3435T has also been linked to higher risk of pharmacoresistance to a wide range of drugs including antiepileptics [14] , antipsychotics, antidepressants [15] , glucocorticoids [16] and methotrexate [17] .…”

Section: Discussionmentioning

confidence: 99%

“…Methotrexate enters the cell mainly via the solute carrier transporter and exits the cell via several channels among which are the ATP binding cassette (ABC) transporters [6] .…”

Section: Introductionmentioning

confidence: 99%

Frequency of ABCB1 C3435T Polymorphism in Rheumatoid Arthritis Patients; Relation to Methotrexate Responsiveness and Methotrexate Adverse Effects

Eissa¹,

Ahmed²,

Ali³

et al. 2023

The Egyptian Journal of Hospital Medicine

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Background: Rheumatoid arthritis (RA) is an inflammatory disease requiring treatment by disease-modifying agents like methotrexate. C3435T is a single nucleotide polymorphism in the ABCB1 gene that affects the expression of the Pglycoprotein responsible for the efflux of several drugs from cells increasing both its action and toxicity. Objective: Examine the frequency of C3435T in RA patients and assess its influence on responsiveness to methotrexate treatment and occurrence of methotrexate adverse effects. Patients and Methods: Genotyping C3435T polymorphism was done by real-time polymerase chain reaction and the frequency of the polymorphism was assessed in a sample of 90 RA patients who have received methotrexate treatment and 90 healthy controls. The prevalence of the polymorphism was also assessed in responders to methotrexate compared to non-responders, and also in patients who suffered from methotrexate side effects compared to those who did not. Results: The CC was the most frequent genotype in patients (47.8%) while the CT was the most frequent in controls (43.3%), however, no association was found between the ABCB1 C3435T genotype and susceptibility to RA under the different genetic models (p>0.05). Even though the patients who responded to methotrexate had a higher frequency of the T allele (38.9%) compared to non-responders (27.8%), the genotype and allele frequency were not associated with response to methotrexate (p>0.05). Also, no association was observed between the frequency of the C3435T polymorphism and experiencing methotrexate-associated adverse effects (p>0.05). Conclusion:The C3435T polymorphism of the ABCB1 gene may not be a genetic risk factor for RA and does not affect responsiveness to methotrexate or affect the occurrence of adverse effects from the drug.

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“…MTX is effective against lung and cervical cancers, where SBRT also appears useful ( Conroy et al, 1976 ; Smyth and Ford, 1981 ). MTX has shown affinity for the SLC transporters organic anion-transporting polypeptide (OATP) and organic anion transporter (OAT), and the ABC transporters multidrug resistance-associated protein (MRP), multidrug resistance protein (MDR), and breast cancer resistance protein (BCRP) ( Hagenbuch and Meier, 2004 ; Nakanishi, 2007 ; Murakami and Mori, 2012 ; Gao et al, 2021 ). While irradiation increases the expressions of MRP1 and MRP2, contributing to the efflux of MTX ( Henness et al, 2002 ; Bartkowiak et al, 2009 ), the effects of irradiation on SLC transporters have not been examined.…”

Section: Introductionmentioning

confidence: 99%

A single high-dose irradiation changes accumulation of methotrexate and gene expression levels of SLC and ABC transporters in cancer cells

et al. 2023

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Chemoradiotherapy is frequently used to treat cancer. Stereotactic body radiotherapy (SBRT) is a single high-dose radiotherapy used to treat a variety of cancers. The anticancer drug methotrexate (MTX) shows affinity for solute carrier (SLC) and ATP-binding cassette (ABC) transporters. This study investigated relationships between accumulation of methotrexate and gene expression levels of solute carrier and ATP-binding cassette transporters in cancer cells after a single and high-dose X-ray irradiation. Cancer cell lines were selected from lung and cervical cancer cell line that are commonly used for stereotactic body radiotherapy and effective with methotrexate. We examined expression levels of organic anion-transporting polypeptide (OATP)1B1, OATP1B3, OATP1B7, and organic anion transporter (OAT)1 as solute carrier transporters and multidrug resistance-associated protein (MRP)1 and MRP2 as ATP-binding cassette transporters, using real-time polymerase chain reaction and accumulation of 3H-MTX in cancer cells after 10-Gy irradiation, assuming stereotactic body radiotherapy. Cells were divided into three groups: Control without irradiation; 4 h after irradiation; and 24 h after irradiation. In control, gene expression levels of OAT1 in all cells was below the limit of measurement. After irradiation, gene expression levels of OATP1B1/1B3/1B7 showed changes in each cell line. Gene expression levels of MRP1/2 tended to increase after irradiation. Gene expression levels of OATP1B1/1B3/1B7 were much lower than those of MRP1/2. Accumulation of 3H-MTX tended to decrease over time after irradiation. Irradiation of cancer cells thus alters gene expression levels of both solute carrier transporters (OATP1B1/1B3/1B7) and ABC transporters (MRP1/2) and decreases accumulation of 3H-MTX in cancer cells over time due to elevated expression of MRP1/2.

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The effects of drug transporters on the efficacy of methotrexate in the treatment of rheumatoid arthritis

Cited by 17 publications

References 125 publications

Osthole regulates N6‐methyladenosine‐modified TGM2 to inhibit the progression of rheumatoid arthritis and associated interstitial lung disease

Osthole regulates N6‐methyladenosine‐modified TGM2 to inhibit the progression of rheumatoid arthritis and associated interstitial lung disease

Frequency of ABCB1 C3435T Polymorphism in Rheumatoid Arthritis Patients; Relation to Methotrexate Responsiveness and Methotrexate Adverse Effects

A single high-dose irradiation changes accumulation of methotrexate and gene expression levels of SLC and ABC transporters in cancer cells

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