Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0QZ0H6)

• DOT Name: Folate receptor alpha (FOLR1)
• Synonyms: FR-alpha; Adult folate-binding protein; FBP; Folate receptor 1; Folate receptor, adult; KB cells FBP; Ovarian tumor-associated antigen MOv18
• Gene Name: FOLR1
• Related Disease: Neurodegenerative syndrome due to cerebral folate transport deficiency
• UniProt ID: FOLR1_HUMAN
• PDB ID: 4KM6; 4KM7; 4KMX; 4LRH; 5IZQ
• Pfam ID: PF03024
• Sequence:
  MAQRMTTQLLLLLVWVAVVGEAQTRIAWARTELLNVCMNAKHHKEKPGPEDKLHEQCRPW
  RKNACCSTNTSQEAHKDVSYLYRFNWNHCGEMAPACKRHFIQDTCLYECSPNLGPWIQQV
  DQSWRKERVLNVPLCKEDCEQWWEDCRTSYTCKSNWHKGWNWTSGFNKCAVGAACQPFHF
  YFPTPTVLCNEIWTHSYKVSNYSRGSGRCIQMWFDPAQGNPNEEVARFYAAAMSGAGPWA
  AWPFLLSLALMLLWLLS
• Function: Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells. Has high affinity for folate and folic acid analogs at neutral pH. Exposure to slightly acidic pH after receptor endocytosis triggers a conformation change that strongly reduces its affinity for folates and mediates their release. Required for normal embryonic development and normal cell proliferation.
• Tissue Specificity: Primarily expressed in tissues of epithelial origin. Expression is increased in malignant tissues. Expressed in kidney, lung and cerebellum. Detected in placenta and thymus epithelium.
• KEGG Pathway:
  Antifolate resistance (hsa01523)
  Endocytosis (hsa04144)
• Reactome Pathway:
  Cargo concentration in the ER (R-HSA-5694530)
  COPI-mediated anterograde transport (R-HSA-6807878)
  COPII-mediated vesicle transport (R-HSA-204005)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodegenerative syndrome due to cerebral folate transport deficiency	DISGEHPQ	Definitive	Autosomal recessive	[1]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Folic acid	DMEMBJC	Approved	Folate receptor alpha (FOLR1) decreases the abundance of Folic acid.	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Floxuridine	DM04LR2	Approved	Folate receptor alpha (FOLR1) affects the response to substance of Floxuridine.	[20]
Raltitrexed	DMT9K8G	Approved	Folate receptor alpha (FOLR1) increases the response to substance of Raltitrexed.	[21]

2 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 Folate receptor alpha (FOLR1).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Folate receptor alpha (FOLR1).	[15]

18 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 Folate receptor alpha (FOLR1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Folate receptor alpha (FOLR1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Folate receptor alpha (FOLR1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Folate receptor alpha (FOLR1).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Folate receptor alpha (FOLR1).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Folate receptor alpha (FOLR1).	[8]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Folate receptor alpha (FOLR1).	[9]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Folate receptor alpha (FOLR1).	[10]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Folate receptor alpha (FOLR1).	[11]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Folate receptor alpha (FOLR1).	[12]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Folate receptor alpha (FOLR1).	[13]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Folate receptor alpha (FOLR1).	[11]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Folate receptor alpha (FOLR1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Folate receptor alpha (FOLR1).	[11]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Folate receptor alpha (FOLR1).	[16]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Folate receptor alpha (FOLR1).	[17]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Folate receptor alpha (FOLR1).	[13]
biochanin A	DM0HPWY	Investigative	biochanin A decreases the expression of Folate receptor alpha (FOLR1).	[18]

References

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• [5] Gamma-irradiation and doxorubicin treatment of normal human cells cause cell cycle arrest via different pathways. Mol Cells. 2005 Dec 31;20(3):331-8.
• [6] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [7] 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.
• [8] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [9] Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Cancer Res. 2006 Mar 1;66(5):2765-77.
• [10] 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.
• [11] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [12] Acute and chronic effects of some dietary bioactive compounds on folic acid uptake and on the expression of folic acid transporters by the human trophoblast cell line BeWo. J Nutr Biochem. 2008 Feb;19(2):91-100. doi: 10.1016/j.jnutbio.2007.01.007. Epub 2007 May 24.
• [13] Folic acid uptake by the human syncytiotrophoblast: interference by pharmacotherapy, drugs of abuse and pathological conditions. Reprod Toxicol. 2009 Dec;28(4):511-20. doi: 10.1016/j.reprotox.2009.07.001. Epub 2009 Jul 16.
• [14] 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.
• [15] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [16] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [17] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [18] Mechanisms of the growth inhibitory effects of the isoflavonoid biochanin A on LNCaP cells and xenografts. Prostate. 2002 Aug 1;52(3):201-12.
• [19] Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism. Am J Hum Genet. 2009 Sep;85(3):354-63. doi: 10.1016/j.ajhg.2009.08.005.
• [20] Folic Acid-Metabolizing Enzymes Regulate the Antitumor Effect of 5-Fluoro-2'-Deoxyuridine in Colorectal Cancer Cell Lines. PLoS One. 2016 Sep 29;11(9):e0163961. doi: 10.1371/journal.pone.0163961. eCollection 2016.
• [21] Synthesis, biological, and antitumor activity of a highly potent 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitor with proton-coupled folate transporter and folate receptor selectivity over the reduced folate carrier that inhibits -glycinamide ribonucleotide formyltransferase. J Med Chem. 2011 Oct 27;54(20):7150-64.