Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFNS0CC)

• DOT Name: Annexin A2 (ANXA2)
• Synonyms: Annexin II; Annexin-2; Calpactin I heavy chain; Calpactin-1 heavy chain; Chromobindin-8; Lipocortin II; Placental anticoagulant protein IV; PAP-IV; Protein I; p36
• Gene Name: ANXA2
• UniProt ID: ANXA2_HUMAN
• PDB ID: 1W7B ; 1XJL ; 2HYU ; 2HYV ; 2HYW ; 4DRW ; 4FTG ; 4HRH ; 5LPU ; 5LPX ; 5LQ0 ; 5LQ2 ; 5N7D ; 5N7F ; 5N7G ; 6TWQ ; 6TWU ; 6TWX ; 6TWY ; 7DTO ; 7EQ7 ; 7NMI ; 7P70 ; 7P71 ; 7P72 ; 7P73 ; 7P74 ; 7PC3 ; 7PC4 ; 7PC5 ; 7PC7 ; 7PC8 ; 7PC9 ; 7PCB ; 7QQL ; 7QQM ; 7QQN ; 7ZVN ; 7ZVX ; 8AEL
• Pfam ID: PF00191
• Sequence:
  MSTVHEILCKLSLEGDHSTPPSAYGSVKAYTNFDAERDALNIETAIKTKGVDEVTIVNIL
  TNRSNAQRQDIAFAYQRRTKKELASALKSALSGHLETVILGLLKTPAQYDASELKASMKG
  LGTDEDSLIEIICSRTNQELQEINRVYKEMYKTDLEKDIISDTSGDFRKLMVALAKGRRA
  EDGSVIDYELIDQDARDLYDAGVKRKGTDVPKWISIMTERSVPHLQKVFDRYKSYSPYDM
  LESIRKEVKGDLENAFLNLVQCIQNKPLYFADRLYDSMKGKGTRDKVLIRIMVSRSEVDM
  LKIRSEFKRKYGKSLYYYIQQDTKGDYQKALLYLCGGDD
• Function: Calcium-regulated membrane-binding protein whose affinity for calcium is greatly enhanced by anionic phospholipids. It binds two calcium ions with high affinity. May be involved in heat-stress response. Inhibits PCSK9-enhanced LDLR degradation, probably reduces PCSK9 protein levels via a translational mechanism but also competes with LDLR for binding with PCSK9 ; (Microbial infection) Binds M.pneumoniae CARDS toxin, probably serves as one receptor for this pathogen. When ANXA2 is down-regulated by siRNA, less toxin binds to human cells and less vacuolization (a symptom of M.pneumoniae infection) is seen.
• KEGG Pathway: Salmonella infection (hsa05132)
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  Dissolution of Fibrin Clot (R-HSA-75205)
  Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation (R-HSA-8950505)
  Smooth Muscle Contraction (R-HSA-445355)

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
Fluorouracil	DMUM7HZ	Approved	Annexin A2 (ANXA2) decreases the response to substance of Fluorouracil.	[17]

41 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 Annexin A2 (ANXA2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Annexin A2 (ANXA2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Annexin A2 (ANXA2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Annexin A2 (ANXA2).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Annexin A2 (ANXA2).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Annexin A2 (ANXA2).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Annexin A2 (ANXA2).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Annexin A2 (ANXA2).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Annexin A2 (ANXA2).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Annexin A2 (ANXA2).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Annexin A2 (ANXA2).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Annexin A2 (ANXA2).	[12]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Annexin A2 (ANXA2).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Annexin A2 (ANXA2).	[13]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Annexin A2 (ANXA2).	[12]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Annexin A2 (ANXA2).	[14]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone affects the expression of Annexin A2 (ANXA2).	[15]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Annexin A2 (ANXA2).	[16]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Annexin A2 (ANXA2).	[17]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of Annexin A2 (ANXA2).	[18]
Ibuprofen	DM8VCBE	Approved	Ibuprofen affects the expression of Annexin A2 (ANXA2).	[19]
Daunorubicin	DMQUSBT	Approved	Daunorubicin decreases the expression of Annexin A2 (ANXA2).	[20]
Acocantherin	DM7JT24	Approved	Acocantherin affects the expression of Annexin A2 (ANXA2).	[21]
Thalidomide	DM70BU5	Approved	Thalidomide decreases the expression of Annexin A2 (ANXA2).	[22]
Cholecalciferol	DMGU74E	Approved	Cholecalciferol affects the expression of Annexin A2 (ANXA2).	[24]
Raltitrexed	DMT9K8G	Approved	Raltitrexed increases the expression of Annexin A2 (ANXA2).	[17]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Annexin A2 (ANXA2).	[25]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Annexin A2 (ANXA2).	[12]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Annexin A2 (ANXA2).	[26]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Annexin A2 (ANXA2).	[27]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Annexin A2 (ANXA2).	[12]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Annexin A2 (ANXA2).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Annexin A2 (ANXA2).	[29]
MG-132	DMKA2YS	Preclinical	MG-132 decreases the expression of Annexin A2 (ANXA2).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Annexin A2 (ANXA2).	[32]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Annexin A2 (ANXA2).	[33]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Annexin A2 (ANXA2).	[34]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Annexin A2 (ANXA2).	[35]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Annexin A2 (ANXA2).	[36]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Annexin A2 (ANXA2).	[37]
CATECHIN	DMY38SB	Investigative	CATECHIN increases the expression of Annexin A2 (ANXA2).	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Dihydroartemisinin	DMBXVMZ	Approved	Dihydroartemisinin affects the binding of Annexin A2 (ANXA2).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Annexin A2 (ANXA2).	[30]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Annexin A2 (ANXA2).	[30]

References

• [1] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [2] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [3] Arsenic trioxide, retinoic acid and Ara-c regulated the expression of annexin II on the surface of APL cells, a novel co-receptor for plasminogen/tissue plasminogen activator. Thromb Res. 2002 Apr 1;106(1):63-70. doi: 10.1016/s0049-3848(02)00075-0.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [8] Protein expression profiling identifies molecular targets of quercetin as a major dietary flavonoid in human colon cancer cells. Proteomics. 2004 Jul;4(7):2160-74.
• [9] [Clinical study on the fibrinolytic activity in patients with acute promyelocytic leukemia]. Zhonghua Xue Ye Xue Za Zhi. 2009 Mar;30(3):145-9.
• [10] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.
• [11] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [12] 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.
• [13] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Proteomic analysis of human adipose tissue after rosiglitazone treatment shows coordinated changes to promote glucose uptake. Obesity (Silver Spring). 2010 Jan;18(1):27-34. doi: 10.1038/oby.2009.208. Epub 2009 Jun 25.
• [16] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [17] 5-Fluorouracil: identification of novel downstream mediators of tumour response. Anticancer Res. 2004 Mar-Apr;24(2A):417-23.
• [18] Consequences of the natural retinoid/retinoid X receptor ligands action in human breast cancer MDA-MB-231 cell line: Focus on functional proteomics. Toxicol Lett. 2017 Nov 5;281:26-34. doi: 10.1016/j.toxlet.2017.09.001. Epub 2017 Sep 5.
• [19] Protein profile in neuroblastoma cells incubated with S- and R-enantiomers of ibuprofen by iTRAQ-coupled 2-D LC-MS/MS analysis: possible action of induced proteins on Alzheimer's disease. Proteomics. 2008 Apr;8(8):1595-607. doi: 10.1002/pmic.200700556.
• [20] [Influence of arsenic trioxide and daunorubicin on the expression of annexin II and fibrinolytic activity in NB4 cells]. Zhonghua Xue Ye Xue Za Zhi. 2010 Dec;31(12):813-6.
• [21] Proteomics analysis of the proliferative effect of low-dose ouabain on human endothelial cells. Biol Pharm Bull. 2007 Feb;30(2):247-53. doi: 10.1248/bpb.30.247.
• [22] [Effects of thalidomide on Annexin II gene regulation]. Zhonghua Xue Ye Xue Za Zhi. 2009 Jul;30(7):464-7.
• [23] Untargeted Proteomics and Systems-Based Mechanistic Investigation of Artesunate in Human Bronchial Epithelial Cells. Chem Res Toxicol. 2015 Oct 19;28(10):1903-13. doi: 10.1021/acs.chemrestox.5b00105. Epub 2015 Sep 21.
• [24] Targeting iron homeostasis induces cellular differentiation and synergizes with differentiating agents in acute myeloid leukemia. J Exp Med. 2010 Apr 12;207(4):731-50. doi: 10.1084/jem.20091488. Epub 2010 Apr 5.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] Up-regulation of endothelial nitric oxide synthase (eNOS), silent mating type information regulation 2 homologue 1 (SIRT1) and autophagy-related genes by repeated treatments with resveratrol in human umbilical vein endothelial cells. Br J Nutr. 2013 Dec;110(12):2150-5.
• [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] MIP-1beta, a novel biomarker for in vitro sensitization test using human monocytic cell line. Toxicol In Vitro. 2006 Aug;20(5):736-42.
• [29] 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.
• [30] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [31] Proteasome inhibition creates a chromatin landscape favorable to RNA Pol II processivity. J Biol Chem. 2020 Jan 31;295(5):1271-1287. doi: 10.1074/jbc.RA119.011174. Epub 2019 Dec 5.
• [32] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [33] 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.
• [34] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [35] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [36] 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.
• [37] Nickel-induced proteins in human HaCaT keratinocytes: annexin II and phosphoglycerate kinase. Toxicology. 2001 Feb 21;159(1-2):33-41. doi: 10.1016/s0300-483x(00)00369-3.
• [38] Epicatechin and a cocoa polyphenolic extract modulate gene expression in human Caco-2 cells. J Nutr. 2004 Oct;134(10):2509-16.