Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUPAU1N)

• DOT Name: Glutaredoxin-3 (GLRX3)
• Synonyms: PKC-interacting cousin of thioredoxin; PICOT; PKC-theta-interacting protein; PKCq-interacting protein; Thioredoxin-like protein 2
• Gene Name: GLRX3
• Related Disease:
  Advanced cancer
  Classic Hodgkin lymphoma
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Colorectal neoplasm
  Cryptococcosis
  Depression
  Hepatocellular carcinoma
  Immunodeficiency
  Kidney cancer
  Lung cancer
  Lung carcinoma
  Neoplasm
  Triple negative breast cancer
  Tuberous sclerosis
  Breast cancer
  Breast carcinoma
• UniProt ID: GLRX3_HUMAN
• PDB ID: 2DIY; 2WZ9; 2YAN; 3ZYW
• Pfam ID: PF00462 ; PF00085
• Sequence:
  MAAGAAEAAVAAVEEVGSAGQFEELLRLKAKSLLVVHFWAPWAPQCAQMNEVMAELAKEL
  PQVSFVKLEAEGVPEVSEKYEISSVPTFLFFKNSQKIDRLDGAHAPELTKKVQRHASSGS
  FLPSANEHLKEDLNLRLKKLTHAAPCMLFMKGTPQEPRCGFSKQMVEILHKHNIQFSSFD
  IFSDEEVRQGLKAYSSWPTYPQLYVSGELIGGLDIIKELEASEELDTICPKAPKLEERLK
  VLTNKASVMLFMKGNKQEAKCGFSKQILEILNSTGVEYETFDILEDEEVRQGLKAYSNWP
  TYPQLYVKGELVGGLDIVKELKENGELLPILRGEN
• Function: Together with BOLA2, acts as a cytosolic iron-sulfur (Fe-S) cluster assembly factor that facilitates [2Fe-2S] cluster insertion into a subset of cytosolic proteins. Acts as a critical negative regulator of cardiac hypertrophy and a positive inotropic regulator. Required for hemoglobin maturation. Does not possess any thyoredoxin activity since it lacks the conserved motif that is essential for catalytic activity.
• Tissue Specificity: Expressed in heart, spleen, testis and, to a lower extent, in thymus and peripheral blood leukocytes. Weakly expressed in lung, placenta, colon and small intestine.
• Reactome Pathway: Iron uptake and transport (R-HSA-917937)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Biomarker	[2]
Colon cancer	DISVC52G	Strong	Altered Expression	[3]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Colorectal neoplasm	DISR1UCN	Strong	Biomarker	[5]
Cryptococcosis	DISDYDTK	Strong	Biomarker	[6]
Depression	DIS3XJ69	Strong	Biomarker	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
Immunodeficiency	DIS093I0	Strong	Biomarker	[8]
Kidney cancer	DISBIPKM	Strong	Biomarker	[9]
Lung cancer	DISCM4YA	Strong	Altered Expression	[9]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[10]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[11]
Tuberous sclerosis	DISEMUGZ	Strong	Altered Expression	[12]
Breast cancer	DIS7DPX1	Limited	Biomarker	[13]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[13]

15 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Glutaredoxin-3 (GLRX3).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Glutaredoxin-3 (GLRX3).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Glutaredoxin-3 (GLRX3).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Glutaredoxin-3 (GLRX3).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glutaredoxin-3 (GLRX3).	[18]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Glutaredoxin-3 (GLRX3).	[19]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Glutaredoxin-3 (GLRX3).	[20]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Glutaredoxin-3 (GLRX3).	[21]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Glutaredoxin-3 (GLRX3).	[22]
Irinotecan	DMP6SC2	Approved	Irinotecan affects the expression of Glutaredoxin-3 (GLRX3).	[23]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Glutaredoxin-3 (GLRX3).	[24]
Benzatropine	DMF7EXL	Approved	Benzatropine increases the expression of Glutaredoxin-3 (GLRX3).	[24]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Glutaredoxin-3 (GLRX3).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Glutaredoxin-3 (GLRX3).	[26]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Glutaredoxin-3 (GLRX3).	[27]

References

• [1] Factors Affecting Adolescents' Willingness to Communicate Symptoms During Cancer Treatment: A Systematic Review from the Children's Oncology Group.J Adolesc Young Adult Oncol. 2019 Apr;8(2):105-113. doi: 10.1089/jayao.2018.0111. Epub 2018 Nov 29.
• [2] Hodgkin's lymphoma cells exhibit high expression levels of the PICOT protein.J Immunotoxicol. 2010 Mar;7(1):8-14. doi: 10.3109/15476910903427654.
• [3] Thioredoxin-like protein 2 is overexpressed in colon cancer and promotes cancer cell metastasis by interaction with ran.Antioxid Redox Signal. 2013 Sep 20;19(9):899-911. doi: 10.1089/ars.2012.4736. Epub 2013 Mar 4.
• [4] Expression of thioredoxins and glutaredoxins in human hepatocellular carcinoma: correlation to cell proliferation, tumor size and metabolic syndrome.Int J Immunopathol Pharmacol. 2014 Apr-Jun;27(2):169-83. doi: 10.1177/039463201402700204.
• [5] Identification and distribution of thioredoxin-like 2 as the antigen for the monoclonal antibody MC3 specific to colorectal cancer.Proteomics. 2008 Jun;8(11):2220-9. doi: 10.1002/pmic.200700770.
• [6] The Monothiol Glutaredoxin Grx4 Regulates Iron Homeostasis and Virulence in Cryptococcus neoformans.mBio. 2018 Dec 4;9(6):e02377-18. doi: 10.1128/mBio.02377-18.
• [7] The effect of chronotherapy on depressive symptoms. Evidence-based practice.Saudi Med J. 2017 May;38(5):457-464. doi: 10.15537/smj.2017.5.18062.
• [8] Thioredoxin-like 2 regulates human cancer cell growth and metastasis via redox homeostasis and NF-B signaling.J Clin Invest. 2011 Jan;121(1):212-25. doi: 10.1172/JCI43144. Epub 2010 Dec 1.
• [9] Preferential overexpression of glutaredoxin3 in human colon and lung carcinoma.Cancer Epidemiol. 2009 Oct;33(3-4):281-7. doi: 10.1016/j.canep.2009.08.006. Epub 2009 Sep 30.
• [10] PICOT binding to chromatin-associated EED negatively regulates cyclin D2 expression by increasing H3K27me3 at the CCND2 gene promoter.Cell Death Dis. 2019 Sep 17;10(10):685. doi: 10.1038/s41419-019-1935-0.
• [11] Identification of the Thioredoxin-Like 2 Autoantibody as a Specific Biomarker for Triple-Negative Breast Cancer.J Breast Cancer. 2018 Mar;21(1):87-90. doi: 10.4048/jbc.2018.21.1.87. Epub 2018 Mar 23.
• [12] Frenolicin B Targets Peroxiredoxin 1 and Glutaredoxin 3 to Trigger ROS/4E-BP1-Mediated Antitumor Effects. Cell Chem Biol. 2019 Mar 21;26(3):366-377.e12. doi: 10.1016/j.chembiol.2018.11.013. Epub 2019 Jan 17.
• [13] Loss of glutaredoxin 3 impedes mammary lobuloalveolar development during pregnancy and lactation.Am J Physiol Endocrinol Metab. 2017 Mar 1;312(3):E136-E149. doi: 10.1152/ajpendo.00150.2016. Epub 2016 Nov 15.
• [14] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [15] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [16] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [19] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [20] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [21] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [22] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [23] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [24] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [25] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [26] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [27] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.