Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9C3KR4)

• DOT Name: Solute carrier family 22 member 18 (SLC22A18)
• Synonyms: Beckwith-Wiedemann syndrome chromosomal region 1 candidate gene A protein; Efflux transporter-like protein; Imprinted multi-membrane-spanning polyspecific transporter-related protein 1; Organic cation transporter-like protein 2; ORCTL-2; Solute carrier family 22 member 1-like; Tumor-suppressing STF cDNA 5 protein; Tumor-suppressing subchromosomal transferable fragment candidate gene 5 protein; p45-Beckwith-Wiedemann region 1 A; p45-BWR1A
• Gene Name: SLC22A18
• Related Disease:
  Adenocarcinoma
  Malaria
  Adult glioblastoma
  Alcohol dependence
  Analgesia
  Arteriosclerosis
  Atherosclerosis
  Autoimmune disease
  Barrett esophagus
  Beckwith-Wiedemann syndrome
  Breast cancer
  Childhood kidney Wilms tumor
  Colorectal carcinoma
  Eosinophilic esophagitis
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Familial multiple trichoepithelioma
  Gastroesophageal reflux disease
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Lung carcinoma
  Myocardial infarction
  Non-small-cell lung cancer
  Paraganglioma
  Renal cell carcinoma
  Smith-Lemli-Opitz syndrome
  Squamous cell carcinoma
  Triple negative breast cancer
  Vitiligo
  Wilms tumor
  Advanced cancer
  Cardiovascular disease
  Breast carcinoma
  Breast neoplasm
  Rhabdomyosarcoma
• UniProt ID: S22AI_HUMAN
• Pfam ID: PF07690
• Sequence:
  MQGARAPRDQGRSPGRMSALGRSSVILLTYVLAATELTCLFMQFSIVPYLSRKLGLDSIA
  FGYLQTTFGVLQLLGGPVFGRFADQRGARAALTLSFLAALALYLLLAAASSPALPGVYLL
  FASRLPGALMHTLPAAQMVITDLSAPEERPAALGRLGLCFGVGVILGSLLGGTLVSAYGI
  QCPAILAALATLLGAVLSFTCIPASTKGAKTDAQAPLPGGPRASVFDLKAIASLLRLPDV
  PRIFLVKVASNCPTGLFMVMFSIISMDFFQLEAAQAGYLMSFFGLLQMVTQGLVIGQLSS
  HFSEEVLLRASVLVFIVVGLAMAWMSSVFHFCLLVPGLVFSLCTLNVVTDSMLIKAVSTS
  DTGTMLGLCASVQPLLRTLGPTVGGLLYRSFGVPVFGHVQVAINTLVLLVLWRKPMPQRK
  DKVR
• Function: May act as a transporter of organic cations based on a proton efflux antiport mechanism. May play a role in the transport of chloroquine and quinidine-related compounds in kidney.
• Tissue Specificity: Expressed at high levels in adult and fetal kidney and liver, and adult colon. Expressed in fetal renal proximal tubules (at protein level). Expressed at lower levels in heart, brain and lung.
• Reactome Pathway:
  Defective SLC22A18 causes lung cancer (LNCR) and embryonal rhabdomyosarcoma 1 (RMSE1) (R-HSA-5619066)
  Organic cation transport (R-HSA-549127)

Molecular Interaction Atlas (MIA) of This DOT

35 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Definitive	Biomarker	[1]
Malaria	DISQ9Y50	Definitive	Biomarker	[2]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[3]
Alcohol dependence	DIS4ZSCO	Strong	Biomarker	[4]
Analgesia	DISK3TVI	Strong	Biomarker	[5]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[6]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[6]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[7]
Barrett esophagus	DIS416Y7	Strong	Biomarker	[8]
Beckwith-Wiedemann syndrome	DISH15GR	Strong	Genetic Variation	[9]
Breast cancer	DIS7DPX1	Strong	Biomarker	[10]
Childhood kidney Wilms tumor	DIS0NMK3	Strong	Genetic Variation	[11]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[12]
Eosinophilic esophagitis	DISR8WSB	Strong	Biomarker	[13]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[14]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[15]
Familial multiple trichoepithelioma	DISKZAUY	Strong	Altered Expression	[16]
Gastroesophageal reflux disease	DISQ8G5S	Strong	Biomarker	[17]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Posttranslational Modification	[18]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[11]
Myocardial infarction	DIS655KI	Strong	Biomarker	[19]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[20]
Paraganglioma	DIS2XXH5	Strong	Biomarker	[21]
Renal cell carcinoma	DISQZ2X8	Strong	Genetic Variation	[22]
Smith-Lemli-Opitz syndrome	DISX9ZUA	Strong	Genetic Variation	[23]
Squamous cell carcinoma	DISQVIFL	Strong	Genetic Variation	[24]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[25]
Vitiligo	DISR05SL	Strong	Genetic Variation	[7]
Wilms tumor	DISB6T16	Strong	Genetic Variation	[11]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[26]
Cardiovascular disease	DIS2IQDX	moderate	Biomarker	[27]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[10]
Breast neoplasm	DISNGJLM	Limited	Altered Expression	[28]
Rhabdomyosarcoma	DISNR7MS	Limited	Genetic Variation	[9]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Solute carrier family 22 member 18 (SLC22A18) affects the response to substance of Etoposide.	[54]
Paclitaxel	DMLB81S	Approved	Solute carrier family 22 member 18 (SLC22A18) decreases the response to substance of Paclitaxel.	[55]

3 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 Solute carrier family 22 member 18 (SLC22A18).	[29]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Solute carrier family 22 member 18 (SLC22A18).	[37]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Solute carrier family 22 member 18 (SLC22A18).	[51]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Solute carrier family 22 member 18 (SLC22A18).	[30]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Solute carrier family 22 member 18 (SLC22A18).	[31]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Solute carrier family 22 member 18 (SLC22A18).	[32]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Solute carrier family 22 member 18 (SLC22A18).	[33]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Solute carrier family 22 member 18 (SLC22A18).	[34]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Solute carrier family 22 member 18 (SLC22A18).	[35]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Solute carrier family 22 member 18 (SLC22A18).	[36]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Solute carrier family 22 member 18 (SLC22A18).	[38]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Solute carrier family 22 member 18 (SLC22A18).	[39]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Solute carrier family 22 member 18 (SLC22A18).	[40]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Solute carrier family 22 member 18 (SLC22A18).	[40]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Solute carrier family 22 member 18 (SLC22A18).	[35]
Selenium	DM25CGV	Approved	Selenium increases the expression of Solute carrier family 22 member 18 (SLC22A18).	[41]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Solute carrier family 22 member 18 (SLC22A18).	[42]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Solute carrier family 22 member 18 (SLC22A18).	[43]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Solute carrier family 22 member 18 (SLC22A18).	[44]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Solute carrier family 22 member 18 (SLC22A18).	[45]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Solute carrier family 22 member 18 (SLC22A18).	[46]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate increases the expression of Solute carrier family 22 member 18 (SLC22A18).	[47]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Solute carrier family 22 member 18 (SLC22A18).	[48]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Solute carrier family 22 member 18 (SLC22A18).	[49]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Solute carrier family 22 member 18 (SLC22A18).	[50]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Solute carrier family 22 member 18 (SLC22A18).	[52]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN decreases the expression of Solute carrier family 22 member 18 (SLC22A18).	[53]

References

• [1] Cytoplasmic overexpression of CD95L in esophageal adenocarcinoma cells overcomes resistance to CD95-mediated apoptosis.Neoplasia. 2011 Mar;13(3):198-205. doi: 10.1593/neo.101304.
• [2] Rapid diagnostic tests as a source of DNA for Plasmodium species-specific real-time PCR.Malar J. 2011 Mar 24;10:67. doi: 10.1186/1475-2875-10-67.
• [3] Silencing SATB1 overcomes temozolomide resistance by downregulating MGMT expression and upregulating SLC22A18 expression in human glioblastoma cells.Cancer Gene Ther. 2018 Dec;25(11-12):309-316. doi: 10.1038/s41417-018-0040-3. Epub 2018 Aug 24.
• [4] Genome-wide association study of alcohol dependence implicates a region on chromosome 11.Alcohol Clin Exp Res. 2010 May;34(5):840-52. doi: 10.1111/j.1530-0277.2010.01156.x. Epub 2010 Mar 1.
• [5] Local infiltration analgesia: a 2-year follow-up of patients undergoing total hip arthroplasty.J Anesth. 2017 Dec;31(6):837-845. doi: 10.1007/s00540-017-2403-6. Epub 2017 Aug 30.
• [6] Intima-Media Thickness in the Carotid and Femoral Arteries for Detection of Arteriosclerosis in Human Immunodeficiency Virus-Positive Individuals.Arq Bras Cardiol. 2017 Jan;108(1):3-11. doi: 10.5935/abc.20160197.
• [7] Evaluation of NLRP1 gene polymorphisms in Vogt-Koyanagi-Harada disease.Jpn J Ophthalmol. 2011 Jan;55(1):57-61. doi: 10.1007/s10384-010-0887-9. Epub 2011 Feb 18.
• [8] Deoxycholic acid promotes development of gastroesophageal reflux disease and Barrett's oesophagus by modulating integrin-v trafficking.J Cell Mol Med. 2017 Dec;21(12):3612-3625. doi: 10.1111/jcmm.13271. Epub 2017 Sep 22.
• [9] Transcriptional map of 170-kb region at chromosome 11p15.5: identification and mutational analysis of the BWR1A gene reveals the presence of mutations in tumor samples.Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3873-8. doi: 10.1073/pnas.95.7.3873.
• [10] Involvement of an Orphan Transporter, SLC22A18, in Cell Growth and Drug Resistance of Human Breast Cancer MCF7 Cells.J Pharm Sci. 2018 Dec;107(12):3163-3170. doi: 10.1016/j.xphs.2018.08.011. Epub 2018 Aug 23.
• [11] Somatic mutation of TSSC5, a novel imprinted gene from human chromosome 11p15.5.Cancer Res. 1998 Sep 15;58(18):4155-9.
• [12] Characterization of SLC22A18 as a tumor suppressor and novel biomarker in colorectal cancer.Oncotarget. 2015 Sep 22;6(28):25368-80. doi: 10.18632/oncotarget.4681.
• [13] FGF9-induced proliferative response to eosinophilic inflammation in oesophagitis.Gut. 2009 Feb;58(2):166-73. doi: 10.1136/gut.2008.157628. Epub 2008 Oct 31.
• [14] Pathogenic BRCA1 mutations may be necessary but not sufficient for tissue genomic heterogeneity: Deep sequencing data from ovarian cancer patients.Gynecol Oncol. 2019 Feb;152(2):375-386. doi: 10.1016/j.ygyno.2018.11.016. Epub 2018 Nov 14.
• [15] Downregulation of long non-coding RNA GAS5 promotes cell proliferation, migration and invasion in esophageal squamous cell carcinoma.Oncol Lett. 2018 Aug;16(2):1801-1808. doi: 10.3892/ol.2018.8797. Epub 2018 May 24.
• [16] The decreased expression of Beclin-1 correlates with progression to esophageal adenocarcinoma: the role of deoxycholic acid.Am J Physiol Gastrointest Liver Physiol. 2012 Apr 15;302(8):G864-72. doi: 10.1152/ajpgi.00340.2011. Epub 2012 Feb 2.
• [17] HCl-induced and ATP-dependent upregulation of TRPV1 receptor expression and cytokine production by human esophageal epithelial cells.Am J Physiol Gastrointest Liver Physiol. 2012 Sep 1;303(5):G635-45. doi: 10.1152/ajpgi.00097.2012. Epub 2012 Jul 12.
• [18] Loss of parental-specific methylation at the IGF2 locus in human hepatocellular carcinoma.J Pathol. 2003 Nov;201(3):473-9. doi: 10.1002/path.1477.
• [19] Cellular FLICE-inhibitory protein protects against cardiac remodelling after myocardial infarction.Basic Res Cardiol. 2012 Jan;107(1):239. doi: 10.1007/s00395-011-0239-z. Epub 2011 Dec 28.
• [20] microRNA-137 functions as a tumor suppressor in human non-small cell lung cancer by targeting SLC22A18.Int J Biol Macromol. 2015 Mar;74:111-8. doi: 10.1016/j.ijbiomac.2014.12.002. Epub 2014 Dec 11.
• [21] Parent-of-origin tumourigenesis is mediated by an essential imprinted modifier in SDHD-linked paragangliomas: SLC22A18 and CDKN1C are candidate tumour modifiers.Hum Mol Genet. 2016 Sep 1;25(17):3715-3728. doi: 10.1093/hmg/ddw218. Epub 2016 Jul 8.
• [22] Promoter CpG island methylation in ion transport mechanisms and associated dietary intakes jointly influence the risk of clear-cell renal cell cancer.Int J Epidemiol. 2017 Apr 1;46(2):622-631. doi: 10.1093/ije/dyw266.
• [23] A highly sensitive method for analysis of 7-dehydrocholesterol for the study of Smith-Lemli-Opitz syndrome.J Lipid Res. 2014 Feb;55(2):329-37. doi: 10.1194/jlr.D043877. Epub 2013 Nov 20.
• [24] Progression of cervical intraepithelial neoplasia to cervical cancer: interactions of cytochrome P450 CYP2D6 EM and glutathione s-transferase GSTM1 null genotypes and cigarette smoking.Br J Cancer. 1994 Oct;70(4):704-8. doi: 10.1038/bjc.1994.378.
• [25] CLImAT-HET: detecting subclonal copy number alterations and loss of heterozygosity in heterogeneous tumor samples from whole-genome sequencing data.BMC Med Genomics. 2017 Mar 15;10(1):15. doi: 10.1186/s12920-017-0255-4.
• [26] Hemoglobins, Hemorphins, and 11p15.5 Chromosomal Region in Cancer Biology and mmunity with Special Emphasis for Brain Tumors.J Neurol Surg A Cent Eur Neurosurg. 2016 May;77(3):247-57. doi: 10.1055/s-0035-1566120. Epub 2016 Mar 2.
• [27] ITM support for patients with chronic respiratory and cardiovascular diseases: a protocol for a randomised controlled trial.BMJ Open. 2019 Mar 1;9(3):e023863. doi: 10.1136/bmjopen-2018-023863.
• [28] Low expression of SLC22A18 predicts poor survival outcome in patients with breast cancer after surgery.Cancer Epidemiol. 2011 Jun;35(3):279-85. doi: 10.1016/j.canep.2010.09.006. Epub 2010 Dec 7.
• [29] 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.
• [30] 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.
• [31] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [32] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [33] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [34] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [35] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [36] 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.
• [37] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [38] Changes in gene expression profiles of multiple myeloma cells induced by arsenic trioxide (ATO): possible mechanisms to explain ATO resistance in vivo. Br J Haematol. 2005 Mar;128(5):636-44.
• [39] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [40] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [41] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [42] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [43] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [44] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [45] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [46] Differential gene expression in human hepatocyte cell lines exposed to the antiretroviral agent zidovudine. Arch Toxicol. 2014 Mar;88(3):609-23. doi: 10.1007/s00204-013-1169-3. Epub 2013 Nov 30.
• [47] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [48] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [49] 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.
• [50] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [51] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [52] Identification of formaldehyde-responsive genes by suppression subtractive hybridization. Toxicology. 2008 Jan 14;243(1-2):224-35.
• [53] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.
• [54] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [55] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.