Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTZ5A5D)

• DOT Name: Intercellular adhesion molecule 3 (ICAM3)
• Synonyms: ICAM-3; CDw50; ICAM-R; CD antigen CD50
• Gene Name: ICAM3
• Related Disease:
  Adult lymphoma
  Advanced cancer
  Barrett esophagus
  Carcinoma of esophagus
  Cervical cancer
  Cervical carcinoma
  Dengue
  Esophageal cancer
  Familial hypercholesterolemia
  Hepatitis C virus infection
  HIV infectious disease
  Immunodeficiency
  Inflammatory bowel disease
  Invasive pulmonary aspergillosis
  Lung cancer
  Lung carcinoma
  Lymphoma
  Mycosis fungoides
  Myocardial infarction
  Neoplasm
  Neoplasm of esophagus
  Obesity
  Osteoarthritis
  Pediatric lymphoma
  Primary biliary cholangitis
  Renal fibrosis
  Rheumatoid arthritis
  Schizophrenia
  Squamous cell carcinoma
  T-cell lymphoma
  Tuberculosis
  B-cell neoplasm
  Metastatic malignant neoplasm
  Primary cutaneous T-cell lymphoma
  Severe acute respiratory syndrome (SARS)
  Systemic lupus erythematosus
• UniProt ID: ICAM3_HUMAN
• PDB ID: 1T0P
• Pfam ID: PF21146 ; PF03921
• Sequence:
  MATMVPSVLWPRACWTLLVCCLLTPGVQGQEFLLRVEPQNPVLSAGGSLFVNCSTDCPSS
  EKIALETSLSKELVASGMGWAAFNLSNVTGNSRILCSVYCNGSQITGSSNITVYRLPERV
  ELAPLPPWQPVGQNFTLRCQVEDGSPRTSLTVVLLRWEEELSRQPAVEEPAEVTATVLAS
  RDDHGAPFSCRTELDMQPQGLGLFVNTSAPRQLRTFVLPVTPPRLVAPRFLEVETSWPVD
  CTLDGLFPASEAQVYLALGDQMLNATVMNHGDTLTATATATARADQEGAREIVCNVTLGG
  ERREARENLTVFSFLGPIVNLSEPTAHEGSTVTVSCMAGARVQVTLDGVPAAAPGQPAQL
  QLNATESDDGRSFFCSATLEVDGEFLHRNSSVQLRVLYGPKIDRATCPQHLKWKDKTRHV
  LQCQARGNPYPELRCLKEGSSREVPVGIPFFVNVTHNGTYQCQASSSRGKYTLVVVMDIE
  AGSSHFVPVFVAVLLTLGVVTIVLALMYVFREHQRSGSYHVREESTYLPLTSMQPTEAMG
  EEPSRAE
• Function: ICAM proteins are ligands for the leukocyte adhesion protein LFA-1 (integrin alpha-L/beta-2). ICAM3 is also a ligand for integrin alpha-D/beta-2. In association with integrin alpha-L/beta-2, contributes to apoptotic neutrophil phagocytosis by macrophages.
• Tissue Specificity: Leukocytes.
• KEGG Pathway: Cell adhesion molecules (hsa04514)
• Reactome Pathway:
  Integrin cell surface interactions (R-HSA-216083)
  CD209 (DC-SIGN) signaling (R-HSA-5621575)
  Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)

Molecular Interaction Atlas (MIA) of This DOT

36 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult lymphoma	DISK8IZR	Strong	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Barrett esophagus	DIS416Y7	Strong	Biomarker	[3]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[3]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[4]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[4]
Dengue	DISKH221	Strong	Biomarker	[5]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[3]
Familial hypercholesterolemia	DISC06IX	Strong	Genetic Variation	[6]
Hepatitis C virus infection	DISQ0M8R	Strong	Genetic Variation	[7]
HIV infectious disease	DISO97HC	Strong	Biomarker	[8]
Immunodeficiency	DIS093I0	Strong	Biomarker	[9]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[10]
Invasive pulmonary aspergillosis	DISIZ0VJ	Strong	Biomarker	[11]
Lung cancer	DISCM4YA	Strong	Biomarker	[2]
Lung carcinoma	DISTR26C	Strong	Biomarker	[2]
Lymphoma	DISN6V4S	Strong	Genetic Variation	[1]
Mycosis fungoides	DIS62RB8	Strong	Biomarker	[12]
Myocardial infarction	DIS655KI	Strong	Biomarker	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[3]
Obesity	DIS47Y1K	Strong	Biomarker	[14]
Osteoarthritis	DIS05URM	Strong	Biomarker	[15]
Pediatric lymphoma	DIS51BK2	Strong	Genetic Variation	[1]
Primary biliary cholangitis	DIS43E0O	Strong	Biomarker	[16]
Renal fibrosis	DISMHI3I	Strong	Biomarker	[17]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[18]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[19]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[4]
T-cell lymphoma	DISSXRTQ	Strong	Biomarker	[20]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[21]
B-cell neoplasm	DISVY326	Limited	Altered Expression	[22]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[23]
Primary cutaneous T-cell lymphoma	DIS35WVW	Limited	Altered Expression	[22]
Severe acute respiratory syndrome (SARS)	DISYW14W	Limited	Biomarker	[24]
Systemic lupus erythematosus	DISI1SZ7	Limited	Genetic Variation	[18]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Intercellular adhesion molecule 3 (ICAM3).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Intercellular adhesion molecule 3 (ICAM3).	[26]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Intercellular adhesion molecule 3 (ICAM3).	[27]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Intercellular adhesion molecule 3 (ICAM3).	[28]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Intercellular adhesion molecule 3 (ICAM3).	[29]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Intercellular adhesion molecule 3 (ICAM3).	[30]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Intercellular adhesion molecule 3 (ICAM3).	[31]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Intercellular adhesion molecule 3 (ICAM3).	[32]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Intercellular adhesion molecule 3 (ICAM3).	[33]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Intercellular adhesion molecule 3 (ICAM3).	[34]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Intercellular adhesion molecule 3 (ICAM3).	[34]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Intercellular adhesion molecule 3 (ICAM3).	[35]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide decreases the expression of Intercellular adhesion molecule 3 (ICAM3).	[36]
Ursodeoxycholic acid	DMCUT21	Approved	Ursodeoxycholic acid affects the expression of Intercellular adhesion molecule 3 (ICAM3).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Intercellular adhesion molecule 3 (ICAM3).	[34]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Intercellular adhesion molecule 3 (ICAM3).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Intercellular adhesion molecule 3 (ICAM3).	[38]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Intercellular adhesion molecule 3 (ICAM3).	[39]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Intercellular adhesion molecule 3 (ICAM3).	[40]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Intercellular adhesion molecule 3 (ICAM3).	[41]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Intercellular adhesion molecule 3 (ICAM3).	[42]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Intercellular adhesion molecule 3 (ICAM3).	[43]

References

• [1] Polymorphisms in integrin genes and lymphoma risk.Leuk Res. 2011 Jul;35(7):968-70. doi: 10.1016/j.leukres.2010.12.012. Epub 2011 Jan 15.
• [2] ICAM3 mediates inflammatory signaling to promote cancer cell stemness.Cancer Lett. 2018 May 28;422:29-43. doi: 10.1016/j.canlet.2018.02.034. Epub 2018 Mar 2.
• [3] Investigation of intercellular adhesion molecules (ICAMs) gene expressions in patients with Barrett's esophagus.Tumour Biol. 2014 May;35(5):4907-12. doi: 10.1007/s13277-014-1644-3. Epub 2014 Jan 29.
• [4] Overexpression of dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin-related protein in cervical cancer and correlation with squamous cell carcinoma antigen.Oncol Lett. 2017 Sep;14(3):2813-2821. doi: 10.3892/ol.2017.6508. Epub 2017 Jun 30.
• [5] HLA and other gene associations with dengue disease severity.Curr Top Microbiol Immunol. 2010;338:99-114. doi: 10.1007/978-3-642-02215-9_8.
• [6] Low-density lipoprotein receptor mutations generate synthetic genome-wide associations.Eur J Hum Genet. 2013 May;21(5):563-6. doi: 10.1038/ejhg.2012.207. Epub 2012 Sep 12.
• [7] The allele 4 of neck region liver-lymph node-specific ICAM-3-grabbing integrin variant is associated with spontaneous clearance of hepatitis C virus and decrease of viral loads.Clin Microbiol Infect. 2014 May;20(5):O325-32. doi: 10.1111/1469-0691.12403. Epub 2013 Nov 6.
• [8] The polymorphisms in DC-SIGNR affect susceptibility to HIV type 1 infection.AIDS Res Hum Retroviruses. 2007 May;23(5):686-92. doi: 10.1089/aid.2006.0212.
• [9] Bispecific chimeric antigen receptors targeting the CD4 binding site and high-mannose Glycans of gp120 optimized for anti-human immunodeficiency virus potency and breadth with minimal immunogenicity.Cytotherapy. 2018 Mar;20(3):407-419. doi: 10.1016/j.jcyt.2017.11.001. Epub 2018 Jan 3.
• [10] Mucosal genome-wide methylation changes in inflammatory bowel disease.Inflamm Bowel Dis. 2012 Nov;18(11):2128-37. doi: 10.1002/ibd.22942. Epub 2012 Mar 14.
• [11] Overexpression of Dendritic Cell-Specific Intercellular Adhesion Molecule-3-Grabbing Nonintegrin in Dendritic Cells Protecting against Aspergillosis.Chin Med J (Engl). 2018 Nov 5;131(21):2575-2582. doi: 10.4103/0366-6999.244103.
• [12] CD20 positive mycosis fungoides: a case report.J Cutan Pathol. 2008 Apr;35(4):398-403. doi: 10.1111/j.1600-0560.2007.00817.x. Epub 2008 Feb 4.
• [13] Biomarkers of vascular injury in relation to myocardial infarction risk: A population-based study.Sci Rep. 2019 Feb 28;9(1):3004. doi: 10.1038/s41598-018-38259-y.
• [14] Elevations of inflammatory proteins in neonatal blood are associated with obesity and overweight among 2-year-old children born extremely premature.Pediatr Res. 2018 Jun;83(6):1110-1119. doi: 10.1038/pr.2017.313. Epub 2018 Jan 10.
• [15] Expression of the dendritic cell-associated C-type lectin DC-SIGN by inflammatory matrix metalloproteinase-producing macrophages in rheumatoid arthritis synovium and interaction with intercellular adhesion molecule 3-positive T cells.Arthritis Rheum. 2003 Feb;48(2):360-9. doi: 10.1002/art.10786.
• [16] Gene expression profiling of early primary biliary cirrhosis: possible insights into the mechanism of action of ursodeoxycholic acid. Liver Int. 2008 Aug;28(7):997-1010. doi: 10.1111/j.1478-3231.2008.01744.x. Epub 2008 Apr 15.
• [17] Human dendritic cell-specific ICAM-3-grabbing non-integrin downstream signaling alleviates renal fibrosis via Raf-1 activation in systemic candidiasis.Cell Mol Immunol. 2019 Mar;16(3):288-301. doi: 10.1038/s41423-018-0161-5. Epub 2018 Aug 20.
• [18] A combined large-scale meta-analysis identifies COG6 as a novel shared risk locus for rheumatoid arthritis and systemic lupus erythematosus.Ann Rheum Dis. 2017 Jan;76(1):286-294. doi: 10.1136/annrheumdis-2016-209436. Epub 2016 May 18.
• [19] Evidence for Association of Cell Adhesion Molecules Pathway and NLGN1 Polymorphisms with Schizophrenia in Chinese Han Population.PLoS One. 2015 Dec 16;10(12):e0144719. doi: 10.1371/journal.pone.0144719. eCollection 2015.
• [20] CD56/neural cell adhesion molecule expression in primary extranodal Ki-1/CD30+ lymphoma. Report of a pediatric case with simultaneous cutaneous and bone localizations.Am J Dermatopathol. 1997 Aug;19(4):384-90. doi: 10.1097/00000372-199708000-00011.
• [21] Association of CD209 and CD209L polymorphisms with tuberculosis infection in a Northeastern Brazilian population.Mol Biol Rep. 2014 Aug;41(8):5449-57. doi: 10.1007/s11033-014-3416-y. Epub 2014 May 30.
• [22] Expression of intercellular adhesion molecule 3 (CDw50) on endothelial cells in cutaneous lymphomas. A comparative study between nodal and cutaneous lymphomas.Am J Dermatopathol. 1997 Aug;19(4):391-5. doi: 10.1097/00000372-199708000-00012.
• [23] ICAM3 mediates tumor metastasis via a LFA-1-ICAM3-ERM dependent manner.Biochim Biophys Acta Mol Basis Dis. 2018 Aug;1864(8):2566-2578. doi: 10.1016/j.bbadis.2018.05.002. Epub 2018 May 3.
• [24] Association of ICAM3 genetic variant with severe acute respiratory syndrome.J Infect Dis. 2007 Jul 15;196(2):271-80. doi: 10.1086/518892. Epub 2007 Jun 5.
• [25] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [26] 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.
• [27] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [28] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [29] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [30] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [31] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [32] 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.
• [33] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [34] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [35] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [36] Comparative gene expression analysis of a chronic myelogenous leukemia cell line resistant to cyclophosphamide using oligonucleotide arrays and response to tyrosine kinase inhibitors. Leuk Res. 2007 Nov;31(11):1511-20.
• [37] Gene expression profiling of early primary biliary cirrhosis: possible insights into the mechanism of action of ursodeoxycholic acid. Liver Int. 2008 Aug;28(7):997-1010. doi: 10.1111/j.1478-3231.2008.01744.x. Epub 2008 Apr 15.
• [38] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [39] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [40] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [41] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [42] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [43] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.