Details of Drug Off-Target (DOT)

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

DOT Name Caspase-2 (CASP2)
Synonyms CASP-2; EC 3.4.22.55; Neural precursor cell expressed developmentally down-regulated protein 2; NEDD-2; Protease ICH-1
Gene Name CASP2
UniProt ID
CASP2_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
1PYO; 2P2C; 3R5J; 3R6G; 3R6L; 3R7B; 3R7N; 3R7S; 3RJM; 6GKF; 6GKG; 6S9K; 6SAD; 6Y8B; 6Y8D
EC Number
3.4.22.55
Pfam ID
PF00619 ; PF00656
Sequence
MAAPSAGSWSTFQHKELMAADRGRRILGVCGMHPHHQETLKKNRVVLAKQLLLSELLEHL
LEKDIITLEMRELIQAKVGSFSQNVELLNLLPKRGPQAFDAFCEALRETKQGHLEDMLLT
TLSGLQHVLPPLSCDYDLSLPFPVCESCPLYKKLRLSTDTVEHSLDNKDGPVCLQVKPCT
PEFYQTHFQLAYRLQSRPRGLALVLSNVHFTGEKELEFRSGGDVDHSTLVTLFKLLGYDV
HVLCDQTAQEMQEKLQNFAQLPAHRVTDSCIVALLSHGVEGAIYGVDGKLLQLQEVFQLF
DNANCPSLQNKPKMFFIQACRGDETDRGVDQQDGKNHAGSPGCEESDAGKEKLPKMRLPT
RSDMICGYACLKGTAAMRNTKRGSWYIEALAQVFSERACDMHVADMLVKVNALIKDREGY
APGTEFHRCKEMSEYCSTLCRHLYLFPGHPPT
Function
Involved in the activation cascade of caspases responsible for apoptosis execution. Might function by either activating some proteins required for cell death or inactivating proteins necessary for cell survival. Associates with PIDD1 and CRADD to form the PIDDosome, a complex that activates CASP2 and triggers apoptosis in response to genotoxic stress.
Tissue Specificity
Expressed at higher levels in the embryonic lung, liver and kidney than in the heart and brain. In adults, higher level expression is seen in the placenta, lung, kidney, and pancreas than in the heart, brain, liver and skeletal muscle.
KEGG Pathway
Apoptosis (hsa04210 )
Reactome Pathway
NADE modulates death signalling (R-HSA-205025 )
TP53 Regulates Transcription of Caspase Activators and Caspases (R-HSA-6803207 )
NOD1/2 Signaling Pathway (R-HSA-168638 )
BioCyc Pathway
MetaCyc:HS02869-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
47 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate affects the expression of Caspase-2 (CASP2). [1]
Ciclosporin DMAZJFX Approved Ciclosporin decreases the expression of Caspase-2 (CASP2). [2]
Doxorubicin DMVP5YE Approved Doxorubicin increases the expression of Caspase-2 (CASP2). [3]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate decreases the expression of Caspase-2 (CASP2). [4]
Estradiol DMUNTE3 Approved Estradiol decreases the expression of Caspase-2 (CASP2). [6]
Arsenic DMTL2Y1 Approved Arsenic increases the expression of Caspase-2 (CASP2). [7]
Quercetin DM3NC4M Approved Quercetin increases the activity of Caspase-2 (CASP2). [8]
Arsenic trioxide DM61TA4 Approved Arsenic trioxide increases the expression of Caspase-2 (CASP2). [9]
Hydrogen peroxide DM1NG5W Approved Hydrogen peroxide increases the activity of Caspase-2 (CASP2). [10]
Carbamazepine DMZOLBI Approved Carbamazepine affects the expression of Caspase-2 (CASP2). [12]
Methotrexate DM2TEOL Approved Methotrexate increases the expression of Caspase-2 (CASP2). [13]
Marinol DM70IK5 Approved Marinol increases the expression of Caspase-2 (CASP2). [14]
Zoledronate DMIXC7G Approved Zoledronate affects the expression of Caspase-2 (CASP2). [15]
Fluorouracil DMUM7HZ Approved Fluorouracil decreases the expression of Caspase-2 (CASP2). [16]
Demecolcine DMCZQGK Approved Demecolcine decreases the expression of Caspase-2 (CASP2). [17]
Etoposide DMNH3PG Approved Etoposide increases the expression of Caspase-2 (CASP2). [3]
Diclofenac DMPIHLS Approved Diclofenac affects the expression of Caspase-2 (CASP2). [12]
Menthol DMG2KW7 Approved Menthol decreases the expression of Caspase-2 (CASP2). [19]
Mitoxantrone DMM39BF Approved Mitoxantrone increases the expression of Caspase-2 (CASP2). [3]
Docetaxel DMDI269 Approved Docetaxel increases the activity of Caspase-2 (CASP2). [21]
Lovastatin DM9OZWQ Approved Lovastatin increases the activity of Caspase-2 (CASP2). [22]
Sodium chloride DMM3950 Approved Sodium chloride increases the expression of Caspase-2 (CASP2). [23]
Phenylephrine DMZHUO5 Approved Phenylephrine affects the activity of Caspase-2 (CASP2). [24]
Amsacrine DMZKYIV Approved Amsacrine increases the expression of Caspase-2 (CASP2). [3]
Clonidine DM6RZ9Q Approved Clonidine increases the activity of Caspase-2 (CASP2). [25]
Mechlorethamine DM0CVXA Approved Mechlorethamine increases the activity of Caspase-2 (CASP2). [26]
Norfloxacin DMIZ6W2 Approved Norfloxacin affects the activity of Caspase-2 (CASP2). [27]
Oxybuprocaine DMI0GDH Approved Oxybuprocaine increases the activity of Caspase-2 (CASP2). [28]
Podofilox DMT2EJP Approved Podofilox increases the activity of Caspase-2 (CASP2). [29]
Resveratrol DM3RWXL Phase 3 Resveratrol increases the expression of Caspase-2 (CASP2). [30]
Curcumin DMQPH29 Phase 3 Curcumin increases the expression of Caspase-2 (CASP2). [31]
Fenretinide DMRD5SP Phase 3 Fenretinide increases the activity of Caspase-2 (CASP2). [32]
Camptothecin DM6CHNJ Phase 3 Camptothecin increases the expression of Caspase-2 (CASP2). [3]
Flupirtine DMPBV9D Phase 2 Flupirtine decreases the expression of Caspase-2 (CASP2). [33]
Phenoxodiol DMBUJVX Phase 1/2 Phenoxodiol increases the activity of Caspase-2 (CASP2). [34]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the expression of Caspase-2 (CASP2). [35]
(+)-JQ1 DM1CZSJ Phase 1 (+)-JQ1 increases the expression of Caspase-2 (CASP2). [36]
Leflunomide DMR8ONJ Phase 1 Trial Leflunomide decreases the expression of Caspase-2 (CASP2). [37]
Terfenadine DM4KLPT Withdrawn from market Terfenadine increases the activity of Caspase-2 (CASP2). [39]
THAPSIGARGIN DMDMQIE Preclinical THAPSIGARGIN increases the activity of Caspase-2 (CASP2). [40]
Homocamptothecin DMBQDA3 Preclinical Homocamptothecin increases the expression of Caspase-2 (CASP2). [3]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of Caspase-2 (CASP2). [41]
3R14S-OCHRATOXIN A DM2KEW6 Investigative 3R14S-OCHRATOXIN A decreases the expression of Caspase-2 (CASP2). [42]
Paraquat DMR8O3X Investigative Paraquat decreases the expression of Caspase-2 (CASP2). [43]
Glyphosate DM0AFY7 Investigative Glyphosate decreases the expression of Caspase-2 (CASP2). [44]
Hydroxydimethylarsine Oxide DMPS2B1 Investigative Hydroxydimethylarsine Oxide increases the expression of Caspase-2 (CASP2). [45]
2,6-Dihydroanthra/1,9-Cd/Pyrazol-6-One DMDN12L Investigative 2,6-Dihydroanthra/1,9-Cd/Pyrazol-6-One decreases the activity of Caspase-2 (CASP2). [46]
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⏷ Show the Full List of 47 Drug(s)
8 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT
Drug Name Drug ID Highest Status Interaction REF
Cisplatin DMRHGI9 Approved Cisplatin increases the cleavage of Caspase-2 (CASP2). [5]
Vorinostat DMWMPD4 Approved Vorinostat increases the cleavage of Caspase-2 (CASP2). [11]
Bortezomib DMNO38U Approved Bortezomib increases the cleavage of Caspase-2 (CASP2). [18]
Topotecan DMP6G8T Approved Topotecan increases the cleavage of Caspase-2 (CASP2). [20]
Dactinomycin DM2YGNW Approved Dactinomycin increases the cleavage of Caspase-2 (CASP2). [5]
M-carboxycinnamic acid bishydroxamide DMHJLPS Preclinical M-carboxycinnamic acid bishydroxamide increases the cleavage of Caspase-2 (CASP2). [11]
Staurosporine DM0E9BR Investigative Staurosporine increases the cleavage of Caspase-2 (CASP2). [5]
Chelerythrine DMCP1G9 Investigative Chelerythrine increases the cleavage of Caspase-2 (CASP2). [47]
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⏷ Show the Full List of 8 Drug(s)
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 increases the phosphorylation of Caspase-2 (CASP2). [38]
Coumarin DM0N8ZM Investigative Coumarin increases the phosphorylation of Caspase-2 (CASP2). [38]
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References

1 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.
2 Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
3 Topoisomerase I and II inhibitors control caspase-2 pre-messenger RNA splicing in human cells. Mol Cancer Res. 2004 Jan;2(1):53-61.
4 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
5 Actinomycin D and staurosporine, potent apoptosis inducers in vitro, are potentially effective chemotherapeutic agents against glioblastoma multiforme. Cancer Chemother Pharmacol. 2000;45(2):149-56. doi: 10.1007/s002800050023.
6 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.
7 Pattern of expression of apoptosis and inflammatory genes in humans exposed to arsenic and/or fluoride. Sci Total Environ. 2010 Jan 15;408(4):760-7. doi: 10.1016/j.scitotenv.2009.11.016. Epub 2009 Dec 4.
8 Quercetin-induced apoptosis of HL-60 cells by reducing PI3K/Akt. Mol Biol Rep. 2012 Jul;39(7):7785-93. doi: 10.1007/s11033-012-1621-0. Epub 2012 May 4.
9 Arsenic trioxide induces different gene expression profiles of genes related to growth and apoptosis in glioma cells dependent on the p53 status. Mol Biol Rep. 2008 Sep;35(3):421-9.
10 Carbamylation and oxidation of proteins lead to apoptotic death of lymphocytes. Chem Biol Interact. 2017 May 25;270:24-32. doi: 10.1016/j.cbi.2017.04.007. Epub 2017 Apr 8.
11 Novel histone deacetylase inhibitors in the treatment of thyroid cancer. Clin Cancer Res. 2005 May 15;11(10):3958-65. doi: 10.1158/1078-0432.CCR-03-0776.
12 Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
13 Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
14 THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
15 Effect of zoledronic acid on oral fibroblasts and epithelial cells: a potential mechanism of bisphosphonate-associated osteonecrosis. Br J Haematol. 2009 Mar;144(5):667-76. doi: 10.1111/j.1365-2141.2008.07504.x. Epub 2008 Nov 20.
16 New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids. Arch Toxicol. 2021 Aug;95(8):2691-2718. doi: 10.1007/s00204-021-03092-2. Epub 2021 Jun 20.
17 Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
18 Proteasome inhibitor PS-341 induces apoptosis through induction of endoplasmic reticulum stress-reactive oxygen species in head and neck squamous cell carcinoma cells. Mol Cell Biol. 2004 Nov;24(22):9695-704. doi: 10.1128/MCB.24.22.9695-9704.2004.
19 Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
20 Topotecan triggers apoptosis in p53-deficient cells by forcing degradation of XIAP and survivin thereby activating caspase-3-mediated Bid cleavage. J Pharmacol Exp Ther. 2010 Jan;332(1):316-25. doi: 10.1124/jpet.109.159962. Epub 2009 Oct 7.
21 Docetaxel-induced prostate cancer cell death involves concomitant activation of caspase and lysosomal pathways and is attenuated by LEDGF/p75. Mol Cancer. 2009 Aug 28;8:68. doi: 10.1186/1476-4598-8-68.
22 Lovastatin induces apoptosis of anaplastic thyroid cancer cells via inhibition of protein geranylgeranylation and de novo protein synthesis. Endocrinology. 2003 Sep;144(9):3852-9. doi: 10.1210/en.2003-0098.
23 Neoplastic-like transformation effect of single-walled and multi-walled carbon nanotubes compared to asbestos on human lung small airway epithelial cells. Nanotoxicology. 2014 Aug;8(5):485-507.
24 Phenylephrine induces necroptosis and apoptosis in corneal epithelial cells dose- and time-dependently. Toxicology. 2019 Dec 1;428:152305. doi: 10.1016/j.tox.2019.152305. Epub 2019 Oct 9.
25 Clonidine Induces Apoptosis of Human Corneal Epithelial Cells through Death Receptors-Mediated, Mitochondria-Dependent Signaling Pathway. Toxicol Sci. 2017 Mar 1;156(1):252-260. doi: 10.1093/toxsci/kfw249.
26 Inhibition of caspase-dependent mitochondrial permeability transition protects airway epithelial cells against mustard-induced apoptosis. Apoptosis. 2006 Sep;11(9):1545-59. doi: 10.1007/s10495-006-8764-1.
27 Norfloxacin induces apoptosis and necroptosis in human corneal epithelial cells. Toxicol In Vitro. 2020 Aug;66:104868. doi: 10.1016/j.tiv.2020.104868. Epub 2020 Apr 19.
28 The cytotoxic effect of oxybuprocaine on human corneal epithelial cells by inducing cell cycle arrest and mitochondria-dependent apoptosis. Hum Exp Toxicol. 2017 Aug;36(8):765-775. doi: 10.1177/0960327116665676. Epub 2016 Sep 1.
29 Polyalkoxybenzenes from plants. 5. Parsley seed extract in synthesis of azapodophyllotoxins featuring strong tubulin destabilizing activity in the sea urchin embryo and cell culture assays. J Med Chem. 2011 Oct 27;54(20):7138-49. doi: 10.1021/jm200737s. Epub 2011 Sep 29.
30 Anti-proliferative and gene expression actions of resveratrol in breast cancer cells in vitro. Oncotarget. 2014 Dec 30;5(24):12891-907.
31 Expression profiles of apoptotic genes induced by curcumin in human breast cancer and mammary epithelial cell lines. Anticancer Res. 2005 Sep-Oct;25(5):3293-302.
32 N-(4-hydroxyphenyl)retinamide induces apoptosis in human retinal pigment epithelial cells: retinoic acid receptors regulate apoptosis, reactive oxygen species generation, and the expression of heme oxygenase-1 and Gadd153. J Cell Physiol. 2006 Dec;209(3):854-65. doi: 10.1002/jcp.20774.
33 Melatonin counteracts ischemia-induced apoptosis in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 1998 Nov;39(12):2374-83.
34 Molecular mechanism of phenoxodiol-induced apoptosis in ovarian carcinoma cells. Cancer. 2006 Feb 1;106(3):599-608. doi: 10.1002/cncr.21633.
35 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.
36 The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models. Oncogene. 2016 Feb 18;35(7):833-45.
37 Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
38 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.
39 H1 histamine receptor antagonists induce genotoxic and caspase-2-dependent apoptosis in human melanoma cells. Carcinogenesis. 2006 Sep;27(9):1787-96. doi: 10.1093/carcin/bgl021. Epub 2006 Mar 28.
40 Diclofenac, a non-steroidal anti-inflammatory drug, suppresses apoptosis induced by endoplasmic reticulum stresses by inhibiting caspase signaling. Neuropharmacology. 2006 Apr;50(5):558-67. doi: 10.1016/j.neuropharm.2005.10.016. Epub 2006 Jan 4.
41 Quercetin and Its Fermented Extract as a Potential Inhibitor of Bisphenol A-Exposed HT-29 Colon Cancer Cells' Viability. Int J Mol Sci. 2023 Mar 15;24(6):5604. doi: 10.3390/ijms24065604.
42 Molecular signatures of cytotoxic effects in human embryonic kidney 293?cells treated with single and mixture of ochratoxin A and citrinin. Food Chem Toxicol. 2019 Jan;123:374-384. doi: 10.1016/j.fct.2018.11.015. Epub 2018 Nov 11.
43 Identification of genes associated with paraquat-induced toxicity in SH-SY5Y cells by PCR array focused on apoptotic pathways. J Toxicol Environ Health A. 2008;71(22):1457-67. doi: 10.1080/15287390802329364.
44 Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
45 Toxicological properties of the thiolated inorganic arsenic and arsenosugar metabolite thio-dimethylarsinic acid in human bladder cells. J Trace Elem Med Biol. 2014 Apr;28(2):138-146. doi: 10.1016/j.jtemb.2013.06.004. Epub 2013 Jul 5.
46 Docetaxel-induced apoptosis of human melanoma is mediated by activation of c-Jun NH2-terminal kinase and inhibited by the mitogen-activated protein kinase extracellular signal-regulated kinase 1/2 pathway. Clin Cancer Res. 2007 Feb 15;13(4):1308-14. doi: 10.1158/1078-0432.CCR-06-2216.
47 An Early and Robust Activation of Caspases Heads Cells for a Regulated Form of Necrotic-like Cell Death. J Biol Chem. 2015 Aug 21;290(34):20841-20855. doi: 10.1074/jbc.M115.644179. Epub 2015 Jun 29.