Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXLD3EC)

• DOT Name: Caspase-6 (CASP6)
• Synonyms: CASP-6; CSP-6; EC 3.4.22.59; Apoptotic protease Mch-2
• Gene Name: CASP6
• UniProt ID: CASP6_HUMAN
• PDB ID: 2WDP; 3K7E; 3NKF; 3NR2; 3OD5; 3P45; 3P4U; 3QNW; 3S70; 3S8E; 3V6L; 3V6M; 4EJF; 4FXO; 4HVA; 4IYR; 4N5D; 4N6G; 4N7J; 4N7M; 4NBK; 4NBL; 4NBN; 6DEU; 6DEV; 8EG5; 8EG6
• EC Number: 3.4.22.59
• Pfam ID: PF00656
• Sequence:
  MSSASGLRRGHPAGGEENMTETDAFYKREMFDPAEKYKMDHRRRGIALIFNHERFFWHLT
  LPERRGTCADRDNLTRRFSDLGFEVKCFNDLKAEELLLKIHEVSTVSHADADCFVCVFLS
  HGEGNHIYAYDAKIEIQTLTGLFKGDKCHSLVGKPKIFIIQACRGNQHDVPVIPLDVVDN
  QTEKLDTNITEVDAASVYTLPAGADFLMCYSVAEGYYSHRETVNGSWYIQDLCEMLGKYG
  SSLEFTELLTLVNRKVSQRRVDFCKDPSAIGKKQVPCFASMLTKKLHFFPKSN
• Function: Cysteine protease that plays essential roles in programmed cell death, axonal degeneration, development and innate immunity. Acts as a non-canonical executioner caspase during apoptosis: localizes in the nucleus and cleaves the nuclear structural protein NUMA1 and lamin A/LMNA thereby inducing nuclear shrinkage and fragmentation. Lamin-A/LMNA cleavage is required for chromatin condensation and nuclear disassembly during apoptotic execution. Acts as a regulator of liver damage by promoting hepatocyte apoptosis: in absence of phosphorylation by AMP-activated protein kinase (AMPK), catalyzes cleavage of BID, leading to cytochrome c release, thereby participating in nonalcoholic steatohepatitis. Cleaves PARK7/DJ-1 in cells undergoing apoptosis. Involved in intrinsic apoptosis by mediating cleavage of RIPK1. Furthermore, cleaves many transcription factors such as NF-kappa-B and cAMP response element-binding protein/CREBBP. Cleaves phospholipid scramblase proteins XKR4 and XKR9. In addition to apoptosis, involved in different forms of programmed cell death. Plays an essential role in defense against viruses by acting as a central mediator of the ZBP1-mediated pyroptosis, apoptosis, and necroptosis (PANoptosis), independently of its cysteine protease activity. PANoptosis is a unique inflammatory programmed cell death, which provides a molecular scaffold that allows the interactions and activation of machinery required for inflammasome/pyroptosis, apoptosis and necroptosis. Mechanistically, interacts with RIPK3 and enhances the interaction between RIPK3 and ZBP1, leading to ZBP1-mediated inflammasome activation and cell death. Plays an essential role in axon degeneration during axon pruning which is the remodeling of axons during neurogenesis but not apoptosis. Regulates B-cell programs both during early development and after antigen stimulation; (Microbial infection) Proteolytically cleaves the N protein of coronoviruses such as MERS-CoV and SARS-CoV. The cleavage of MERS-CoV N-protein leads to two fragments and modulates coronavirus replication by regulating IFN signaling. The two fragments produced by the cleavage interact with IRF3 inhibiting its nuclear translocation after activation and reduce the expression of IFNB and IFN-stimulated genes. The same mechanism seems to be used by other coronaviruses such as SARS-CoV and SARS-CoV-2 to enhance their replication.
• KEGG Pathway:
  Apoptosis (hsa04210)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  Caspase-mediated cleavage of cytoskeletal proteins (R-HSA-264870)
  Breakdown of the nuclear lamina (R-HSA-352238)
  TP53 Regulates Transcription of Caspase Activators and Caspases (R-HSA-6803207)
  Apoptotic cleavage of cellular proteins (R-HSA-111465)
• BioCyc Pathway: MetaCyc:HS06561-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	Caspase-6 (CASP6) affects the response to substance of Topotecan.	[42]
Hydroxydimethylarsine Oxide	DMPS2B1	Investigative	Caspase-6 (CASP6) affects the binding of Hydroxydimethylarsine Oxide.	[43]

42 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 Caspase-6 (CASP6).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Caspase-6 (CASP6).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Caspase-6 (CASP6).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Caspase-6 (CASP6).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Caspase-6 (CASP6).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Caspase-6 (CASP6).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Caspase-6 (CASP6).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Caspase-6 (CASP6).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Caspase-6 (CASP6).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Caspase-6 (CASP6).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Caspase-6 (CASP6).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Caspase-6 (CASP6).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Caspase-6 (CASP6).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Caspase-6 (CASP6).	[14]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Caspase-6 (CASP6).	[15]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Caspase-6 (CASP6).	[16]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the activity of Caspase-6 (CASP6).	[17]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Caspase-6 (CASP6).	[18]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Caspase-6 (CASP6).	[19]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Caspase-6 (CASP6).	[20]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Caspase-6 (CASP6).	[22]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Caspase-6 (CASP6).	[23]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Caspase-6 (CASP6).	[14]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the activity of Caspase-6 (CASP6).	[24]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Caspase-6 (CASP6).	[25]
Mitoxantrone	DMM39BF	Approved	Mitoxantrone increases the activity of Caspase-6 (CASP6).	[26]
Lovastatin	DM9OZWQ	Approved	Lovastatin increases the activity of Caspase-6 (CASP6).	[27]
Deoxycholic acid	DM3GYAL	Approved	Deoxycholic acid increases the activity of Caspase-6 (CASP6).	[28]
Ketamine	DMT5HA4	Approved	Ketamine increases the activity of Caspase-6 (CASP6).	[29]
Cladribine	DM3JDRP	Approved	Cladribine increases the activity of Caspase-6 (CASP6).	[30]
Bendamustine hydrochloride	DMFH15Z	Approved	Bendamustine hydrochloride increases the activity of Caspase-6 (CASP6).	[26]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the activity of Caspase-6 (CASP6).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Caspase-6 (CASP6).	[11]
PF-3758309	DM36PKZ	Phase 1	PF-3758309 decreases the expression of Caspase-6 (CASP6).	[32]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Caspase-6 (CASP6).	[33]
Terfenadine	DM4KLPT	Withdrawn from market	Terfenadine increases the activity of Caspase-6 (CASP6).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Caspase-6 (CASP6).	[35]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Caspase-6 (CASP6).	[36]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Caspase-6 (CASP6).	[37]
acrolein	DMAMCSR	Investigative	acrolein increases the activity of Caspase-6 (CASP6).	[38]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl decreases the expression of Caspase-6 (CASP6).	[39]
Apicidin	DM83WVF	Investigative	Apicidin increases the activity of Caspase-6 (CASP6).	[40]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bortezomib	DMNO38U	Approved	Bortezomib increases the cleavage of Caspase-6 (CASP6).	[21]
Staurosporine	DM0E9BR	Investigative	Staurosporine increases the cleavage of Caspase-6 (CASP6).	[41]
Chelerythrine	DMCP1G9	Investigative	Chelerythrine increases the cleavage of Caspase-6 (CASP6).	[41]

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] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] Response rate of fibrosarcoma cells to cytotoxic drugs on the expression level correlates to the therapeutic response rate of fibrosarcomas and is mediated by regulation of apoptotic pathways. BMC Cancer. 2005 Jul 7;5:74. doi: 10.1186/1471-2407-5-74.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [9] 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.
• [10] Application of cDNA microarray to the study of arsenic-induced liver diseases in the population of Guizhou, China. Toxicol Sci. 2001 Jan;59(1):185-92.
• [11] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [12] Arsenic trioxide (As(2)O(3)) induced apoptosis and its mechanisms in a human esophageal squamous carcinoma cell line. Chin Med J (Engl). 2002 Feb;115(2):280-5.
• [13] 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.
• [14] 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.
• [15] A dual role of p21waf1/cip1 gene in apoptosis of HEp-2 treated with cisplatin or methotrexate. Cancer Gene Ther. 2008 Sep;15(9):576-90. doi: 10.1038/cgt.2008.28. Epub 2008 May 16.
• [16] DNA methyltransferase inhibitor 5-aza-CdR enhances the radiosensitivity of gastric cancer cells. Cancer Sci. 2009 Jan;100(1):181-8. doi: 10.1111/j.1349-7006.2008.01004.x. Epub 2008 Nov 25.
• [17] Antitumor effects of aminobisphosphonates on renal cell carcinoma cell lines. J Urol. 2006 Nov;176(5):2255-61. doi: 10.1016/j.juro.2006.07.053.
• [18] 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.
• [19] Effects of folate deficiency on gene expression in the apoptosis and cancer pathways in colon cancer cells. Carcinogenesis. 2006 May;27(5):916-24. doi: 10.1093/carcin/bgi312. Epub 2005 Dec 16.
• [20] Cannabidiol Modulates the Immunophenotype and Inhibits the Activation of the Inflammasome in Human Gingival Mesenchymal Stem Cells. Front Physiol. 2016 Nov 24;7:559. doi: 10.3389/fphys.2016.00559. eCollection 2016.
• [21] Inhibition of p38alpha MAPK enhances proteasome inhibitor-induced apoptosis of myeloma cells by modulating Hsp27, Bcl-X(L), Mcl-1 and p53 levels in vitro and inhibits tumor growth in vivo. Leukemia. 2006 Jun;20(6):1017-27. doi: 10.1038/sj.leu.2404200.
• [22] Survival of retinal pigment epithelium after exposure to prolonged oxidative injury: a detailed gene expression and cellular analysis. Invest Ophthalmol Vis Sci. 2004 Oct;45(10):3767-77.
• [23] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [24] Indomethacin induces apoptosis in 786-O renal cell carcinoma cells by activating mitogen-activated protein kinases and AKT. Eur J Pharmacol. 2007 Jun 1;563(1-3):49-60. doi: 10.1016/j.ejphar.2007.01.071. Epub 2007 Feb 8.
• [25] 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.
• [26] Synergistic effects of chemotherapeutic drugs in lymphoma cells are associated with down-regulation of inhibitor of apoptosis proteins (IAPs), prostate-apoptosis-response-gene 4 (Par-4), death-associated protein (Daxx) and with enforced caspase activation. Biochem Pharmacol. 2003 Sep 1;66(5):711-24. doi: 10.1016/s0006-2952(03)00410-6.
• [27] Lovastatin-induced apoptosis in thyroid cells: involvement of cytochrome c and lamin B. Eur J Endocrinol. 2001 Nov;145(5):645-50. doi: 10.1530/eje.0.1450645.
• [28] Prevention of deoxycholate-induced gastric apoptosis by aspirin: roles of NF-kappaB and PKC signaling. J Surg Res. 2008 Mar;145(1):66-73. doi: 10.1016/j.jss.2007.04.039. Epub 2007 Jul 20.
• [29] Apoptotic insults to human HepG2 cells induced by S-(+)-ketamine occurs through activation of a Bax-mitochondria-caspase protease pathway. Br J Anaesth. 2009 Jan;102(1):80-9. doi: 10.1093/bja/aen322. Epub 2008 Nov 9.
• [30] Cladribine induces apoptosis in human leukaemia cells by caspase-dependent and -independent pathways acting on mitochondria. Biochem J. 2001 Nov 1;359(Pt 3):537-46. doi: 10.1042/0264-6021:3590537.
• [31] Resveratrol displays converse dose-related effects on 5-fluorouracil-evoked colon cancer cell apoptosis: the roles of caspase-6 and p53. Cancer Biol Ther. 2008 Aug;7(8):1305-12. doi: 10.4161/cbt.7.8.6302. Epub 2008 Aug 16.
• [32] Inhibition of neuroblastoma proliferation by PF-3758309, a small-molecule inhibitor that targets p21-activated kinase 4. Oncol Rep. 2017 Nov;38(5):2705-2716. doi: 10.3892/or.2017.5989. Epub 2017 Sep 22.
• [33] 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.
• [34] 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.
• [35] Effect of bisphenol-A on the expression of selected genes involved in cell cycle and apoptosis in the OVCAR-3 cell line. Toxicol Lett. 2011 Apr 10;202(1):30-5. doi: 10.1016/j.toxlet.2011.01.015. Epub 2011 Jan 26.
• [36] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [37] Use of human neuroblastoma SH-SY5Y cells to evaluate glyphosate-induced effects on oxidative stress, neuronal development and cell death signaling pathways. Environ Int. 2020 Feb;135:105414. doi: 10.1016/j.envint.2019.105414. Epub 2019 Dec 23.
• [38] Acrolein induces a cellular stress response and triggers mitochondrial apoptosis in A549 cells. Chem Biol Interact. 2009 Oct 7;181(2):154-67. doi: 10.1016/j.cbi.2009.07.001. Epub 2009 Jul 9.
• [39] DNA fragmentation factor 40 expression in T cells confers sensibility to tributyltin-induced apoptosis. Toxicology. 2019 Oct 1;426:152255. doi: 10.1016/j.tox.2019.152255. Epub 2019 Aug 8.
• [40] Modulation of cell cycles and apoptosis by apicidin in estrogen receptor (ER)-positive and-negative human breast cancer cells. Chem Biol Interact. 2008 Apr 15;172(3):235-44. doi: 10.1016/j.cbi.2008.01.007. Epub 2008 Feb 1.
• [41] 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.
• [42] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [43] Get phases from arsenic anomalous scattering: de novo SAD phasing of two protein structures crystallized in cacodylate buffer. PLoS One. 2011;6(9):e24227. doi: 10.1371/journal.pone.0024227. Epub 2011 Sep 2.