Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPN90H0)

• DOT Name: SPARC (SPARC)
• Synonyms: Basement-membrane protein 40; BM-40; Osteonectin; ON; Secreted protein acidic and rich in cysteine
• Gene Name: SPARC
• Related Disease:
  Osteogenesis imperfecta type 17
  Osteogenesis imperfecta type 4
• UniProt ID: SPRC_HUMAN
• PDB ID: 1BMO; 1NUB; 1SRA; 2V53
• Pfam ID: PF09289 ; PF00050 ; PF10591
• Sequence:
  MRAWIFFLLCLAGRALAAPQQEALPDETEVVEETVAEVTEVSVGANPVQVEVGEFDDGAE
  ETEEEVVAENPCQNHHCKHGKVCELDENNTPMCVCQDPTSCPAPIGEFEKVCSNDNKTFD
  SSCHFFATKCTLEGTKKGHKLHLDYIGPCKYIPPCLDSELTEFPLRMRDWLKNVLVTLYE
  RDEDNNLLTEKQKLRVKKIHENEKRLEAGDHPVELLARDFEKNYNMYIFPVHWQFGQLDQ
  HPIDGYLSHTELAPLRAPLIPMEHCTTRFFETCDLDNDKYIALDEWAGCFGIKQKDIDKD
  LVI
• Function: Appears to regulate cell growth through interactions with the extracellular matrix and cytokines. Binds calcium and copper, several types of collagen, albumin, thrombospondin, PDGF and cell membranes. There are two calcium binding sites; an acidic domain that binds 5 to 8 Ca(2+) with a low affinity and an EF-hand loop that binds a Ca(2+) ion with a high affinity.
• Reactome Pathway:
  Nuclear signaling by ERBB4 (R-HSA-1251985)
  ECM proteoglycans (R-HSA-3000178)
  Scavenging by Class H Receptors (R-HSA-3000497)
  Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Osteogenesis imperfecta type 17	DISYFC01	Strong	Autosomal recessive	[1]
Osteogenesis imperfecta type 4	DIS8S46L	Supportive	Autosomal dominant	[1]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	SPARC (SPARC) affects the response to substance of Temozolomide.	[34]
Fluorouracil	DMUM7HZ	Approved	SPARC (SPARC) increases the response to substance of Fluorouracil.	[35]
DTI-015	DMXZRW0	Approved	SPARC (SPARC) affects the response to substance of DTI-015.	[34]
(S)-Norfluoxetine	DM8ZTPF	Investigative	SPARC (SPARC) increases the Fracture ADR of (S)-Norfluoxetine.	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of SPARC (SPARC).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of SPARC (SPARC).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of SPARC (SPARC).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of SPARC (SPARC).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of SPARC (SPARC).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of SPARC (SPARC).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of SPARC (SPARC).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of SPARC (SPARC).	[10]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of SPARC (SPARC).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of SPARC (SPARC).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of SPARC (SPARC).	[13]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of SPARC (SPARC).	[14]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of SPARC (SPARC).	[15]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of SPARC (SPARC).	[16]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of SPARC (SPARC).	[17]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of SPARC (SPARC).	[18]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of SPARC (SPARC).	[19]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of SPARC (SPARC).	[20]
Palbociclib	DMD7L94	Approved	Palbociclib increases the expression of SPARC (SPARC).	[21]
Bexarotene	DMOBIKY	Approved	Bexarotene increases the expression of SPARC (SPARC).	[22]
LY2835219	DM93VBZ	Approved	LY2835219 increases the expression of SPARC (SPARC).	[21]
Magnesium	DMU4ORS	Approved	Magnesium increases the expression of SPARC (SPARC).	[23]
Berberine	DMC5Q8X	Phase 4	Berberine increases the expression of SPARC (SPARC).	[24]
Isoflavone	DM7U58J	Phase 4	Isoflavone affects the expression of SPARC (SPARC).	[25]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of SPARC (SPARC).	[26]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of SPARC (SPARC).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of SPARC (SPARC).	[29]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of SPARC (SPARC).	[31]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of SPARC (SPARC).	[32]
Arachidonic acid	DMUOQZD	Investigative	Arachidonic acid decreases the expression of SPARC (SPARC).	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of SPARC (SPARC).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of SPARC (SPARC).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of SPARC (SPARC).	[30]

References

• [1] Recessive osteogenesis imperfecta caused by missense mutations in SPARC. Am J Hum Genet. 2015 Jun 4;96(6):979-85. doi: 10.1016/j.ajhg.2015.04.021. Epub 2015 May 28.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] 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.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Effects of the endocrine-disrupting chemical DDT on self-renewal and differentiation of human mesenchymal stem cells. Environ Health Perspect. 2015 Jan;123(1):42-8.
• [9] 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.
• [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] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [13] Frequent inactivation of SPARC by promoter hypermethylation in colon cancers. Int J Cancer. 2007 Aug 1;121(3):567-75. doi: 10.1002/ijc.22706.
• [14] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [15] Folic acid modulates cancer-associated micro RNAs and inflammatory mediators in neoplastic and non-neoplastic colonic cells in a different way. Mol Nutr Food Res. 2017 Dec;61(12). doi: 10.1002/mnfr.201700260. Epub 2017 Nov 9.
• [16] Comparison of replicative senescence and stress-induced premature senescence combining differential display and low-density DNA arrays. FEBS Lett. 2005 Jul 4;579(17):3651-9. doi: 10.1016/j.febslet.2005.05.056.
• [17] 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.
• [18] Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009 Aug 21;138(4):645-659. doi: 10.1016/j.cell.2009.06.034. Epub 2009 Aug 13.
• [19] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [20] 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.
• [21] Biological specificity of CDK4/6 inhibitors: dose response relationship, in vivo signaling, and composite response signature. Oncotarget. 2017 Jul 4;8(27):43678-43691. doi: 10.18632/oncotarget.18435.
• [22] Identification of biomarkers modulated by the rexinoid LGD1069 (bexarotene) in human breast cells using oligonucleotide arrays. Cancer Res. 2006 Dec 15;66(24):12009-18.
• [23] Effect of surface chemical modification of bioceramic on phenotype of human bone-derived cells. J Biomed Mater Res. 1999 Mar 15;44(4):389-96. doi: 10.1002/(sici)1097-4636(19990315)44:4<389::aid-jbm4>3.0.co;2-o.
• [24] Berberine promotes bone marrow-derived mesenchymal stem cells osteogenic differentiation via canonical Wnt/-catenin signaling pathway. Toxicol Lett. 2016 Jan 5;240(1):68-80. doi: 10.1016/j.toxlet.2015.10.007. Epub 2015 Oct 22.
• [25] Soy isoflavones alter expression of genes associated with cancer progression, including interleukin-8, in androgen-independent PC-3 human prostate cancer cells. J Nutr. 2006 Jan;136(1):75-82.
• [26] Effect of resveratrol on matrix metalloproteinase-2 (MMP-2) and Secreted Protein Acidic and Rich in Cysteine (SPARC) on human cultured glioblastoma cells. Biomed Pharmacother. 2005 Aug;59(7):359-64. doi: 10.1016/j.biopha.2005.06.001.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] 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.
• [31] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [32] Overexpression of heme oxygenase-1 increases human osteoblast stem cell differentiation. J Bone Miner Metab. 2010 May;28(3):276-88.
• [33] Arachidonic acid-induced gene expression in colon cancer cells. Carcinogenesis. 2006 Oct;27(10):1950-60.
• [34] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.
• [35] Genome-wide expression analysis of therapy-resistant tumors reveals SPARC as a novel target for cancer therapy. J Clin Invest. 2005 Jun;115(6):1492-502. doi: 10.1172/JCI23002. Epub 2005 May 12.
• [36] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.