Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSB42BR)

• DOT Name: Neutrophil gelatinase-associated lipocalin (LCN2)
• Synonyms: NGAL; 25 kDa alpha-2-microglobulin-related subunit of MMP-9; Lipocalin-2; Oncogene 24p3; Siderocalin; p25
• Gene Name: LCN2
• UniProt ID: NGAL_HUMAN
• PDB ID: 1DFV ; 1L6M ; 1NGL ; 1QQS ; 1X71 ; 1X89 ; 1X8U ; 3BY0 ; 3CBC ; 3CMP ; 3DSZ ; 3DTQ ; 3FW4 ; 3FW5 ; 3HWD ; 3HWE ; 3HWF ; 3HWG ; 3I0A ; 3K3L ; 3PEC ; 3PED ; 3T1D ; 3TF6 ; 3TZS ; 3U0D ; 4GH7 ; 4IAW ; 4IAX ; 4K19 ; 4MVI ; 4MVK ; 4MVL ; 4QAE ; 4ZFX ; 4ZHC ; 4ZHD ; 4ZHF ; 4ZHG ; 4ZHH ; 5JR8 ; 5KHP ; 5KIC ; 5KID ; 5MHH ; 5N47 ; 5N48 ; 5NKN ; 6GQZ ; 6GR0 ; 6O5D ; 6QMU ; 6S8V ; 6SUA ; 6Z2C ; 6Z6Z
• Pfam ID: PF00061
• Sequence:
  MPLGLLWLGLALLGALHAQAQDSTSDLIPAPPLSKVPLQQNFQDNQFQGKWYVVGLAGNA
  ILREDKDPQKMYATIYELKEDKSYNVTSVLFRKKKCDYWIRTFVPGCQPGEFTLGNIKSY
  PGLTSYLVRVVSTNYNQHAMVFFKKVSQNREYFKITLYGRTKELTSELKENFIRFSKSLG
  LPENHIVFPVPIDQCIDG
• Function: Iron-trafficking protein involved in multiple processes such as apoptosis, innate immunity and renal development. Binds iron through association with 2,3-dihydroxybenzoic acid (2,3-DHBA), a siderophore that shares structural similarities with bacterial enterobactin, and delivers or removes iron from the cell, depending on the context. Iron-bound form (holo-24p3) is internalized following binding to the SLC22A17 (24p3R) receptor, leading to release of iron and subsequent increase of intracellular iron concentration. In contrast, association of the iron-free form (apo-24p3) with the SLC22A17 (24p3R) receptor is followed by association with an intracellular siderophore, iron chelation and iron transfer to the extracellular medium, thereby reducing intracellular iron concentration. Involved in apoptosis due to interleukin-3 (IL3) deprivation: iron-loaded form increases intracellular iron concentration without promoting apoptosis, while iron-free form decreases intracellular iron levels, inducing expression of the proapoptotic protein BCL2L11/BIM, resulting in apoptosis. Involved in innate immunity; limits bacterial proliferation by sequestering iron bound to microbial siderophores, such as enterobactin. Can also bind siderophores from M.tuberculosis.
• Tissue Specificity: Detected in neutrophils (at protein level) . Expressed in bone marrow and in tissues that are prone to exposure to microorganism . High expression is found in bone marrow as well as in uterus, prostate, salivary gland, stomach, appendix, colon, trachea and lung . Expressed in the medullary tubules of the kidney . Not found in the small intestine or peripheral blood leukocytes .
• KEGG Pathway: IL-17 sig.ling pathway (hsa04657)
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  Metal sequestration by antimicrobial proteins (R-HSA-6799990)
  Iron uptake and transport (R-HSA-917937)
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
DTI-015	DMXZRW0	Approved	Neutrophil gelatinase-associated lipocalin (LCN2) increases the response to substance of DTI-015.	[23]

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 Neutrophil gelatinase-associated lipocalin (LCN2).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Neutrophil gelatinase-associated lipocalin (LCN2).	[18]

22 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 Neutrophil gelatinase-associated lipocalin (LCN2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Neutrophil gelatinase-associated lipocalin (LCN2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Neutrophil gelatinase-associated lipocalin (LCN2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Neutrophil gelatinase-associated lipocalin (LCN2).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Neutrophil gelatinase-associated lipocalin (LCN2).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Neutrophil gelatinase-associated lipocalin (LCN2).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Neutrophil gelatinase-associated lipocalin (LCN2).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Neutrophil gelatinase-associated lipocalin (LCN2).	[9]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Neutrophil gelatinase-associated lipocalin (LCN2).	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Neutrophil gelatinase-associated lipocalin (LCN2).	[3]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Neutrophil gelatinase-associated lipocalin (LCN2).	[11]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Neutrophil gelatinase-associated lipocalin (LCN2).	[12]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Neutrophil gelatinase-associated lipocalin (LCN2).	[13]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the expression of Neutrophil gelatinase-associated lipocalin (LCN2).	[3]
Bicalutamide	DMZMSPF	Approved	Bicalutamide increases the expression of Neutrophil gelatinase-associated lipocalin (LCN2).	[14]
Tacrolimus	DMZ7XNQ	Approved	Tacrolimus increases the expression of Neutrophil gelatinase-associated lipocalin (LCN2).	[15]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of Neutrophil gelatinase-associated lipocalin (LCN2).	[16]
Coprexa	DMA0WEK	Phase 3	Coprexa decreases the expression of Neutrophil gelatinase-associated lipocalin (LCN2).	[17]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Neutrophil gelatinase-associated lipocalin (LCN2).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Neutrophil gelatinase-associated lipocalin (LCN2).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Neutrophil gelatinase-associated lipocalin (LCN2).	[21]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid increases the expression of Neutrophil gelatinase-associated lipocalin (LCN2).	[3]

3 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil increases the secretion of Neutrophil gelatinase-associated lipocalin (LCN2).	[9]
Gentamicin	DMKINJO	Approved	Gentamicin decreases the secretion of Neutrophil gelatinase-associated lipocalin (LCN2).	[4]
1-anilinonaphthalene-8-sulfonic acid	DMNGY0E	Investigative	1-anilinonaphthalene-8-sulfonic acid affects the binding of Neutrophil gelatinase-associated lipocalin (LCN2).	[22]

References

• [1] 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.
• [2] 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.
• [3] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
• [4] Neutrophil gelatinase-associated lipocalin production negatively correlates with HK-2 cell impairment: Evaluation of NGAL as a marker of toxicity in HK-2 cells. Toxicol In Vitro. 2017 Mar;39:52-57. doi: 10.1016/j.tiv.2016.11.012. Epub 2016 Nov 22.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] Arsenic trioxide induces apoptosis in NB-4, an acute promyelocytic leukemia cell line, through up-regulation of p73 via suppression of nuclear factor kappa B-mediated inhibition of p73 transcription and prevention of NF-kappaB-mediated induction of XIAP, cIAP2, BCL-XL and survivin. Med Oncol. 2010 Sep;27(3):833-42. doi: 10.1007/s12032-009-9294-9. Epub 2009 Sep 10.
• [8] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [9] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [10] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [11] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [12] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [13] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [14] Microarray analysis of bicalutamide action on telomerase activity, p53 pathway and viability of prostate carcinoma cell lines. J Pharm Pharmacol. 2005 Jan;57(1):83-92.
• [15] Tacrolimus-induced nephrotoxicity in mice is associated with microRNA deregulation. Arch Toxicol. 2018 Apr;92(4):1539-1550. doi: 10.1007/s00204-018-2158-3. Epub 2018 Jan 23.
• [16] Regulation of lipocalin-2 gene by the cancer chemopreventive retinoid 4-HPR. Int J Cancer. 2006 Oct 1;119(7):1599-606.
• [17] Copper deprivation enhances the chemosensitivity of pancreatic cancer to rapamycin by mTORC1/2 inhibition. Chem Biol Interact. 2023 Sep 1;382:110546. doi: 10.1016/j.cbi.2023.110546. Epub 2023 Jun 7.
• [18] 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.
• [19] Lipocalin 2, a new GADD153 target gene, as an apoptosis inducer of endoplasmic reticulum stress in lung cancer cells. Toxicol Appl Pharmacol. 2012 Sep 15;263(3):330-7. doi: 10.1016/j.taap.2012.07.005. Epub 2012 Jul 16.
• [20] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [22] Comparative ligand-binding analysis of ten human lipocalins. Biochim Biophys Acta. 2006 Feb;1764(2):161-73. doi: 10.1016/j.bbapap.2005.12.006. Epub 2006 Jan 6.
• [23] Down-regulation of lipocalin 2 contributes to chemoresistance in glioblastoma cells. J Neurochem. 2009 Dec;111(5):1238-51. doi: 10.1111/j.1471-4159.2009.06410.x. Epub 2009 Oct 5.