Expression of Methotrexate Transporters and Metabolizing Enzymes in Rheumatoid Synovial Tissue

Stamp, Lisa K.; Hazlett, Jody; Highton, John; Hessian, Paul A.

doi:10.3899/jrheum.130066

Cited by 14 publications

(9 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The reduction in MTX influx as a result of alterations in RFC is one of the main reasons decreasing the therapeutic efficacy of the drug. Further, many reports have been revealed that the MTX serves as a substrate for Pgp [3,18].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Ameliorated in vitro anticancer efficacy of methotrexate d-α-Tocopheryl polyethylene glycol 1000 succinate ester against breast cancer cells

et al. 2019

View full text Add to dashboard Cite

Background: Methotrexate (MTX), a folate anti-metabolite, has been used widely in the treatment of plenty of malignancies. However, the clinical use is limited because of its poor water solubility (BCS class II drug), nonspecific distribution, drug resistance, short circulation half-life, and toxicity. The objective of the present research was to synthesize the ester prodrug of MTX with D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) and characterize for in vitro anticancer efficacy. Results: The FTIR and NMR results revealed the successful synthesis of the prodrug. The assay and saturation solubility of the prodrug is found to be 23 ± 2.5% and 6.7 ± 1.3 mg/mL (MTX equivalent) respectively. The CMC of the prodrug in distilled water at room temperature is found to be 36.9 ± 2.6 μg/mL. The prepared prodrug micelles showed a mean particle size of 166 ± 10 nm (PDI, 0.325 ± 0.09). Further, the TEM results confirmed the self-assembling character of the prodrug into micelles with a nearly spherical shape. The prodrug caused the significantly (p < 0.01) less hemolysis (16.8 ± 1.5%) when compared to plain MTX solution and significantly higher (p < 0.01) in vitro cytotoxicity, cell cycle arresting, and apoptosis against human breast cancer cells (MCF-7 and MDA-MB-231). Conclusion: Our study results revealed the remarkable in vitro anticancer activity of MTX following its esterification with TPGS. However, further, in vivo studies are needed to prove its efficacy against different cancers.

show abstract

Section: Discussionmentioning

confidence: 99%

“…However, the clinical use of MTX is limited because of its poor water solubility (BCS class II drug), nonspecific distribution, drug resistance, short circulation half-life, and toxicity. Besides, the multidrug resistance (MDR) is the prime cause of chemotherapy failure, including MTX [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Ameliorated in vitro anticancer efficacy of methotrexate d-α-Tocopheryl polyethylene glycol 1000 succinate ester against breast cancer cells

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Studies in mouse synovial cells show that SLC19A1 expression was down-regulated by inflammatory components, such as IL-6 [ 18 ]. In RA patients, there was a significant negative correlation between SLC19A1 expression and ESR [ 10 ]. These studies lead us to believe that SLC19A1 down-regulation is associated with inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, from the study using synovial tissues obtained from RA patients, Stamp et al. noted a negative correlation between the ESR (erythrocyte sedimentation rate) and expressions levels of some MTX pathway genes [ 10 ]. These findings led us to wonder whether MTX pathway genes are influenced by the NFKBIE gene.…”

Section: Introductionmentioning

confidence: 99%

ImpairedNFKBIEgene function decreases cellular uptake of methotrexate by down-regulatingSLC19A1expression in a human rheumatoid arthritis cell line

Imamura

Yoshina

Ikari

et al. 2016

Modern Rheumatology

View full text Add to dashboard Cite

Objective: A non-synonymous single nucleotide polymorphism (nsSNP, rs2233434, Val194Ala) in the NFKBIE (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, epsilon) gene is known to be a rheumatoid arthritis (RA) susceptibility polymorphism in the Japanese RA population and could be closely associated with nuclear factor kappaB (NF-κB) activity. Inflammation caused by RA is sometimes associated with changes in expression levels of MTX (methotrexate) pathway-related genes. It is of interest to examine whether the NFKBIE gene had any influences on the mode of MTX action. Methods: Both knockdown of NFKBIE gene expression and overexpression of wild-type NFKBIE and Val194Ala mutation were performed. A transfected human RA synovial cell line was cultured and then gene expressions in the MTX pathway were measured. In addition, we measured the uptake and efflux of MTX derivatives under the NFKBIE knockdown condition. Results: Knockdown of NFKBIE reduced the mRNA for SLC19A1, a main MTX membrane transporter, and the intracellular accumulations of MTX derivatives. Moreover, our experiments also confirmed that overexpression of Val194Ala mutant NFKBIE decreased the SLC19A1 mRNA when compared to that of wild-type NFKBIE. Conclusions: We suggest that the impairment of NFKBIE gene function can reduce the uptake of MTX into cells, suggesting that the gene is an important factor for the RA outcome.

show abstract

“…46) This expression was significantly higher in patients treated with MTX than in those untreated. Considering its clinical use in the treatment for RA, the delivery or entry process of MTX to target cells such as lymphocytes and macrophages in the rheumatoid synovial tissues is of substantial interest, and it is likely that RFC1 plays a major role in that.…”

Section: Transporters Involved In the Pharmacokinetics Of Mtxmentioning

confidence: 96%

Molecular Basis for Pharmacokinetics and Pharmacodynamics of Methotrexate in Rheumatoid Arthritis Therapy

Inoue

Yuasa

2014

Drug Metabolism and Pharmacokinetics

121

View full text Add to dashboard Cite

Methotrexate (MTX) is a derivative of folic acid (folate) and commonly used as an anchor drug for the treatment of rheumatoid arthritis (RA). The pharmacokinetics (PK) and pharmacodynamics (PD) of MTX entirely depends on the function of specific transporters that belong to the two major superfamilies, solute carrier transporters and ATP-binding cassette transporters. Several transporters have been identified as being able to mediate the transport of MTX, and suggested to be involved in the disposition in the body and in the regulation of intracellular metabolism in target cells, together with several enzymes involved in folate metabolism. Thus, drug-drug interactions through the transporters and their genetic polymorphisms may alter the PK and PD of MTX, resulting in an interpatient variability of efficacy. This review summarizes the PK and PD of MTX, particularly in relation to RA therapy and focuses on the roles of transporters involved in PK and PD with the aim of facilitating an understanding of the molecular basis of the mechanism of MTX action to achieve its effective use in RA therapy.

show abstract

Expression of Methotrexate Transporters and Metabolizing Enzymes in Rheumatoid Synovial Tissue

Cited by 14 publications

References 10 publications

Ameliorated in vitro anticancer efficacy of methotrexate d-α-Tocopheryl polyethylene glycol 1000 succinate ester against breast cancer cells

Ameliorated in vitro anticancer efficacy of methotrexate d-α-Tocopheryl polyethylene glycol 1000 succinate ester against breast cancer cells

ImpairedNFKBIEgene function decreases cellular uptake of methotrexate by down-regulatingSLC19A1expression in a human rheumatoid arthritis cell line

Molecular Basis for Pharmacokinetics and Pharmacodynamics of Methotrexate in Rheumatoid Arthritis Therapy

Contact Info

Product

Resources

About