Drug Information

Drug (ID: DG00039) and It's Reported Resistant Information

• Name: Sulfasalazine
• Synonyms: Sulfasalazine; 599-79-1; Salicylazosulfapyridine; Salazosulfapyridine; Azulfidine; Asulfidine; Salazopyridin; Sulcolon; Azopyrin; Accucol; Colo-Pleon; Salazopiridazin; Salisulf; Reupirin; Benzosulfa; Azopyrine; Salazosulfapyridin; Sulfasalazina; w-t Sasp oral; Sulfasalazinum; Sulfasalazin; Azulfidine EN; Sulfazalazine; Azulfidine EN-tabs; Salazosulfapiridina; Sas-500; Salazosulfapyridinum; Azosulfidin; SASP; Salazo-sulfapyridinum; 5-(p-(2-Pyridylsulfamyl)phenylazo)salicylic acid; SAS-500; Sulfasalizine
• Indication:
  In total 2 Indication(s)
  Irritable bowel syndrome [ICD-11: DD91]; Approved; [1]
  Rheumatoid arthritis [ICD-11: FA20]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Rheumatoid arthritis [ICD-11: FA20]; [2]
• Target: ATP-binding cassette transporter G2 (ABCG2); ABCG2_HUMAN; [1]
• Target: Nuclear factor NF-kappa-B (NFKB); NFKB1_HUMAN NFKB2_HUMAN TF65_HUMAN RELB_HUMAN REL_HUMAN; [1]
• Formula: C18H14N4O5S
• IsoSMILES: C1=CC=NC(=C1)NS(=O)(=O)C2=CC=C(C=C2)N=NC3=CC(=C(C=C3)O)C(=O)O
• InChI: 1S/C18H14N4O5S/c23-16-9-6-13(11-15(16)18(24)25)21-20-12-4-7-14(8-5-12)28(26,27)22-17-3-1-2-10-19-17/h1-11,23H,(H,19,22)(H,24,25)
• InChIKey: NCEXYHBECQHGNR-UHFFFAOYSA-N
• PubChem CID: 5339
• ChEBI ID: CHEBI:9334
• TTD Drug ID: D02ZTJ
• VARIDT ID: DR00201
• INTEDE ID: DR1513
• DrugBank ID: DB00795

Type(s) of Resistant Mechanism of This Drug

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Ovarian cancer [ICD-11: 2C73]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Cystine/glutamate transporter (SLC7A11) [3]

• Metabolic Type: Redox metabolism
• Sensitive Disease: Ovarian clear cell carcinoma [ICD-11: 2C73.00]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Caov-3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• In Vitro Model: HAC-2 cells; Ovary; Homo sapiens (Human); CVCL_8354
• In Vitro Model: RMG-1 cells; Ascites; Homo sapiens (Human); CVCL_1662
• In Vitro Model: SKOV-3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: TOV21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: This study demonstrated that combined treatment with paclitaxel (PTX) and the xCT inhibitor sulfasalazine (SAS) significantly enhanced cytotoxicity more than the individual drugs did in OCCC cells. Treatment with PTX and SAS induced apoptosis more effectively than did individual drug treatments in the cells with significant generation of ROS.

Unspecified carcinoma of unspecified site [ICD-11: 2D41]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Cystine/glutamate transporter (SLC7A11) [4]

• Sensitive Disease: krasg12c inhibitor resistant tumors [ICD-11: 2D41]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK 293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: MiaPaCa-2 cells; Blood; Homo sapiens (Human); CVCL_0428
• In Vitro Model: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: NCI-H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Calu-1 cells; Lung; Homo sapiens (Human); CVCL_0608
• In Vivo Model: BALB/c athymic nude mice model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR; Western blot assay
• Experiment for Drug Resistance: Cell viability assay; Immunohistochemical assay; Xenograft mouse assay
• Mechanism Description: The clinical success of KRASG12C inhibitors (G12Ci) including AMG510 and MRTX849 is limited by the eventual development of acquired resistance. A novel and effective treatment to revert or target this resistance is urgent. To this end, we established G12Ci (AMG510 and MRTX849) resistant KRASG12C mutant cancer cell lines and screened with an FDA-approved drug library. We found the ferroptosis inducers including sorafenib and lapatinib stood out with an obvious growth inhibition in the G12Ci resistant cells. Mechanistically, the G12Ci resistant cells exhibited reactivation of MAPK signaling, which repressed SOX2-mediated expression of cystine transporter SLC7A11 and iron exporter SLC40A1. Consequently, the low intracellular GSH level but high iron content engendered hypersensitivity of these resistant tumors to ferroptosis inducers. Ectopic overexpression of SOX2 or SLC7A11 and SLC40A1 conferred resistance to ferroptosis in the G12Ci resistant cells. Ferroptosis induced by sulfasalazine (SAS) achieved obvious inhibition on the tumor growth of xenografts derived from AMG510-resistant KRASG12C-mutant cells.

ICD-13: Digestive system diseases

Ulcerative colitis [ICD-11: DD71]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [1]

• Sensitive Disease: Ulcerative colitis [ICD-11: DD71.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: IPS cells; Colon; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Ussing chamber system assay
• Mechanism Description: Digoxin and fexofenadine (each 5 uM) were selected as P-gp substrates, and sulfasalazine and rosuvastatin (each 5 uM) were selected as BCRP substrates to evaluate the efflux transport mediated by P-gp and BCRP. PSC833 (15 uM) and ko143 (15 uM) were used as typical inhibitors of P-gp and BCRP, respectively. Serosal-to-mucosal transport of all the tested P-gp and BCRP substrate drugs was significantly decreased or tended to decrease in the presence of P-gp/BCRP inhibitor cocktail.

ICD-15: Musculoskeletal/connective-tissue diseases

Rheumatoid arthritis [ICD-11: FA20]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [2]

• Resistant Disease: Rheumatoid arthritis [ICD-11: FA20.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: MTX is a substrate for eight ABC transporters. In vitro studies demonstrated that RAFLS treated with MTX had higher ABCB1 expression levels than controls, with a positive correlation between ABCB1 expression levels and RA treatment duration. In addition to MTX, other DMARDs (e.g. sulfasalazine, leflunomide, bucillamine, azathioprine), glucocorticoids (e.g. betamethasone, dexamethasone), and NSAIDs (e.g. celecoxib and indomethacin) are also substrates of ABC transporters.

References

• Ref 1: Characterization of the Human Intestinal Drug Transport with Ussing Chamber System Incorporating Freshly Isolated Human Jejunum. Drug Metab Dispos. 2021 Jan;49(1):84-93. doi: 10.1124/dmd.120.000138. Epub 2020 Oct 21.
• Ref 2: Drug-resistance in rheumatoid arthritis: the role of p53 gene mutations, ABC family transporters and personal factors .Curr Opin Pharmacol. 2020 Oct;54:59-71. doi: 10.1016/j.coph.2020.08.002. Epub 2020 Sep 14. 10.1016/j.coph.2020.08.002
• Ref 3: Mechanism of Cell Death by Combined Treatment with an xCT Inhibitor and Paclitaxel: An Alternative Therapeutic Strategy for Patients with Ovarian Clear Cell Carcinoma. Int J Mol Sci. 2023 Jul 22;24(14):11781.
• Ref 4: Reactivation of MAPK-SOX2 pathway confers ferroptosis sensitivity in KRAS(G12C) inhibitor resistant tumors. Redox Biol. 2024 Dec;78:103419.