Drug Details

General Information of the Drug (ID: DR1258)
Name
Methotrexate
Synonyms
diazinon; Dimpylate; 333-41-5; Diazinone; Oleodiazinon; Neocidol; Spectracide; Diazitol; Nedcidol; Dassitox; Ciazinon; Ektoband; Nucidol; Flytrol; Exodin; Galesan; Bazuden; Diazol; Diazide; Sarolex; Dazzel; Dacutox; Basudin; Antigal; Dicid; Alfa-tox; Diazajet; Dimpylat; Garden Tox; Neocidol (oil); Bassadinon; Terminator; Kayazol; Dizinon; Disonex; Compass; Meodinon; Kayazinon; Drawizon; Nipsan; Dyzol; Diazinon ag 500; Knox-out; Neodinon; Optimizer; Dimpylatum; Delzinon; Dizictol; Dipofene; Dizinil; Bazudin; Srolex; Basudin 10 G; Geigy 24480; Basudin S; Knox
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Molecular Type
Small molecule
Disease Leukaemia [ICD-11: 2A60-2B33] Approved [1]
Structure
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2D MOL

3D MOL

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Formula
C20H22N8O5
PubChem CID
126941
Canonical SMILES
CN(CC1=CN=C2C(=N1)C(=NC(=N2)N)N)C3=CC=C(C=C3)C(=O)NC(CCC(=O)O)C(=O)O
InChI
1S/C20H22N8O5/c1-28(9-11-8-23-17-15(24-11)16(21)26-20(22)27-17)12-4-2-10(3-5-12)18(31)25-13(19(32)33)6-7-14(29)30/h2-5,8,13H,6-7,9H2,1H3,(H,25,31)(H,29,30)(H,32,33)(H4,21,22,23,26,27)/t13-/m0/s1
InChIKey
FBOZXECLQNJBKD-ZDUSSCGKSA-N
CAS Number
CAS 59-05-2
GDSC
Methotrexate
TTD Drug ID
D0SV8E
DrugBank ID
DB00563
Combinatorial Therapeutic Effect(s) Validated Clinically or Experimentally
    α. A List of Natural Product(s) Able to Enhance the Efficacy of This Drug
          17-beta-Estradiol      Homo sapiens     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [2]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    In-vitro Model MDA-MB-436 CVCL_0623 Invasive breast carcinoma Homo sapiens
MCF-7 CVCL_0031 Invasive breast carcinoma Homo sapiens
                    Experimental
                    Result(s)		 17-beta-oestradiol partially reversed the anti-proliferative effects of MTX in the MDA-MB-436 line and potentiated growth inhibition in the E2 responsive cells.
          Acitretin      Homo sapiens     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [3]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    In-vivo Model Male K14-VEGF mice (10 weeks old) were used in this study.
                    Experimental
                    Result(s)		 The acitretin and methotrexate combination therapy for psoriasis vulgaris achieves higher effectiveness and less liver fibrosis.
          Astilbin      Smilax glabra     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [4]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Up-regulation Expression ERK1  Molecule Info 
Pathway MAP
Up-regulation Expression p105  Molecule Info 
Pathway MAP
Up-regulation Expression STAT1  Molecule Info 
Pathway MAP
                    In-vivo Model Specific-pathogen-free, eight-week-old male DBA/1J mice, and Eight-week-old C57BL/6 mice were used in this study.
                    Experimental
                    Result(s)		 Astilbin is a valuable candidate for low-dose MTX combined therapy in RA via increasing A2AAR/adenosine system and decreasing ERK/NFKappaB/STATs signals.
          Bucillamine      Homo sapiens     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [5]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    In-vivo Model Clinical Trial
                    Experimental
                    Result(s)		 The triple DMARD combination therapy provided a new treatment option for those patients for whom treatment with biologics is difficult.
          Glycyrrhizin      Glycyrrhiza glabra     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [6]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Experimental
                    Result(s)		 Methotrexate and compound glycyrrhizin can be an effective alternative therapy in the treatment of erythrodermic psoriasis with BP.
          Green tea catechins      Theaceae     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [7]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    In-vitro Model Pseudomonas aeruginosa Microorganism model Pseudomonas aeruginosa
Staphylococcus aureus Microorganism model Staphylococcus aureus
                    Experimental
                    Result(s)		 Green tea extract and catechins potentiated the antimicrobial action of gentamicin against some clinical isolates of S. aureus and standard P. aeruginosa strains.
          Silibinin      Carduus marianus     Click to Show/Hide the Molecular Data of This NP
                 Augmenting Drug Sensitivity     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [8]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    In-vitro Model Human rhabdomyosarcoma Rhabdomyosarcoma Homo sapiens
                    Experimental
                    Result(s)		 Silibinin improves the cytotoxicity of methotrexate in chemo resistant human rhabdomyosarcoma cell lines.
          Sinomenine      Sinomenium     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [9]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression IL6  Molecule Info 
Pathway MAP
Down-regulation Expression MMP-9  Molecule Info 
Pathway MAP
                    In-vivo Model Arthritis was induced by immunizing with CII in female Srague-Dawley rats.
                    Experimental
                    Result(s)		 SIN and MTX have additive effects, decreasing inflammation and joint damage in CIA rats by modulating osteoclast-related cytokines. These results are indicative of the combined effect of SIN and MTX for anti-arthritic treatment in RA.
          Vinblastine      Catharanthus roseus     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [10]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Experimental
                    Result(s)		 Low-dose chemotherapy with methotrexate and vinblastine for 1 year was effective and well tolerated by adult patients with aggressive, recurrent fibromatosis.
          Vincristine      Catharanthus roseus     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [11]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    In-vitro Model MOLT-3 CVCL_0624 Adult T acute lymphoblastic leukemia Homo sapiens
                    Experimental
                    Result(s)		 Simultaneous exposure of VCR and MTX produced subadditive or mutually protective interactions.
    β. A List of Natural Product(s) Able to Decrease the Adverse Effect of This Drug
          Chlorogenic acid      Imperata cylindrica     Click to Show/Hide the Molecular Data of This NP
                 Decreasing Adverse Drug Reaction     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [12]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Up-regulation Expression BAX  Molecule Info 
Pathway MAP
Down-regulation Expression BCL-2  Molecule Info 
Pathway MAP
Up-regulation Cleavage CASP3  Molecule Info 
Pathway MAP
Up-regulation Cleavage CASP9  Molecule Info 
Pathway MAP
Down-regulation Expression COX-2  Molecule Info 
Pathway MAP
Down-regulation Expression GPT  Molecule Info 
Pathway MAP
Down-regulation Expression GPT  Molecule Info 
Pathway MAP
Down-regulation Expression LDHA  Molecule Info 
Pathway MAP
Down-regulation Expression NOS2  Molecule Info 
Pathway MAP
                    Biological
                    Regulation		 Attennuation Pro-inflammatory and apoptotic mediators
Improvement Antioxidant competence
                    In-vivo Model 6-8 weeks old Male Wistar rats (150-200 g) were use in this study.
                    Experimental
                    Result(s)		 CGA has perfective effect against MTX-induced liver injury.
          Gentiopicroside      Gentiana     Click to Show/Hide the Molecular Data of This NP
                 Decreasing Adverse Drug Reaction     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [13]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression IL1B  Molecule Info 
Pathway MAP
Down-regulation Expression IL6  Molecule Info 
Pathway MAP
Down-regulation Expression TNF  Molecule Info 
Pathway MAP
                    In-vivo Model SD rats (200 g +/- 20 g) were used in this study.
                    Experimental
                    Result(s)		 Gentiopicroside (GPS) could exert hepatoprotective effects on leflunomide (LEF)- and/or methotrexate (MTX)-treated arthritic rats.
Target and Pathway
Target(s) Proton-coupled folate transporter (SLC46A1)  Molecule Info  [14]
Reduced folate carrier protein (SLC19A1)  Molecule Info  [15]
References
Reference 1 Pain reduction with oral methotrexate in knee osteoarthritis, a pragmatic phase iii trial of treatment effectiveness (PROMOTE): study protocol for ... Trials. 2015 Mar 4;16:77.
Reference 2 Oestrogen receptor status and the response of human breast cancer cell lines to a combination of methotrexate and 17-beta oestradiol. Br J Cancer. 1985 Mar;51(3):365-9.
Reference 3 The acitretin and methotrexate combination therapy for psoriasis vulgaris achieves higher effectiveness and less liver fibrosis. Pharmacol Res. 2017 Jul;121:158-168.
Reference 4 A novel combination of astilbin and low-dose methotrexate respectively targeting A 2A AR and its ligand adenosine for the treatment of collagen-induced arthritis. Biochem Pharmacol. 2018 Jul;153:269-281.
Reference 5 The usefulness of a new triple combination treatment utilizing methotrexate, salazosulfapyridine, and bucillamine in rheumatoid arthritis. Mod Rheumatol. 2016;26(1):51-6.
Reference 6 Erythrodermic psoriasis with bullous pemphigoid: combination treatment with methotrexate and compound glycyrrhizin. Diagn Pathol. 2014 May 29;9:102.
Reference 7 Effect of Catechins, Green tea Extract and Methylxanthines in Combination with Gentamicin Against Staphylococcus aureus and Pseudomonas aeruginosa: - Combination therapy against resistant bacteria. J Pharmacopuncture. 2016 Dec;19(4):312-318.
Reference 8 Silibinin improves the cytotoxicity of methotrexate in chemo resistant human rhabdomyosarcoma cell lines. Saudi Med J. 2013 Nov;34(11):1145-50.
Reference 9 A combination of sinomenine and methotrexate reduces joint damage of collagen induced arthritis in rats by modulating osteoclast-related cytokines. Int Immunopharmacol. 2014 Jan;18(1):135-41.
Reference 10 Combination chemotherapy with methotrexate and vinblastine for surgically unresectable, aggressive fibromatosis. Jpn J Clin Oncol. 2016 Sep;46(9):845-9.
Reference 11 Effects of vincristine in combination with methotrexate and other antitumor agents in human acute lymphoblastic leukemia cells in culture. Cancer Res. 1988 Jan 15;48(2):351-6.
Reference 12 Protective effect of Chlorogenic acid against methotrexate induced oxidative stress, inflammation and apoptosis in rat liver: An experimental approach. Chem Biol Interact. 2017 Jun 25;272:80-91.
Reference 13 Hepatoprotective effect of gentiopicroside in combination with leflunomide and/or methotrexate in arthritic rats. Life Sci. 2021 Jan 15;265:118689.
Reference 14 URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1213).
Reference 15 Increased activity of a novel low pH folate transporter associated with lipophilic antifolate resistance in chinese hamster ovary cells. J Biol Chem. 1998 Apr 3;273(14):8106-11.
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