Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUFS8CF)

• DOT Name: Lymphotoxin-beta (LTB)
• Synonyms: LT-beta; Tumor necrosis factor C; TNF-C; Tumor necrosis factor ligand superfamily member 3
• Gene Name: LTB
• UniProt ID: TNFC_HUMAN
• PDB ID: 4MXW
• Pfam ID: PF00229
• Sequence:
  MGALGLEGRGGRLQGRGSLLLAVAGATSLVTLLLAVPITVLAVLALVPQDQGGLVTETAD
  PGAQAQQGLGFQKLPEEEPETDLSPGLPAAHLIGAPLKGQGLGWETTKEQAFLTSGTQFS
  DAEGLALPQDGLYYLYCLVGYRGRAPPGGGDPQGRSVTLRSSLYRAGGAYGPGTPELLLE
  GAETVTPVLDPARRQGYGPLWYTSVGFGGLVQLRRGERVYVNISHPDMVDFARGKTFFGA
  VMVG
• Function: Cytokine that binds to LTBR/TNFRSF3. May play a specific role in immune response regulation. Provides the membrane anchor for the attachment of the heterotrimeric complex to the cell surface. Isoform 2 is probably non-functional.
• Tissue Specificity: Spleen and thymus.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  NF-kappa B sig.ling pathway (hsa04064)
  Rheumatoid arthritis (hsa05323)
• Reactome Pathway:
  TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway (R-HSA-5676594)
  TNFR2 non-canonical NF-kB pathway (R-HSA-5668541)

Molecular Interaction Atlas (MIA) of This DOT

23 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 Lymphotoxin-beta (LTB).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of Lymphotoxin-beta (LTB).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Lymphotoxin-beta (LTB).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Lymphotoxin-beta (LTB).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Lymphotoxin-beta (LTB).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Lymphotoxin-beta (LTB).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Lymphotoxin-beta (LTB).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Lymphotoxin-beta (LTB).	[8]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Lymphotoxin-beta (LTB).	[7]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Lymphotoxin-beta (LTB).	[9]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Lymphotoxin-beta (LTB).	[10]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the expression of Lymphotoxin-beta (LTB).	[11]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Lymphotoxin-beta (LTB).	[12]
Sanguinarine	DMDINFS	Approved	Sanguinarine increases the expression of Lymphotoxin-beta (LTB).	[6]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Lymphotoxin-beta (LTB).	[13]
Chloroquine	DMSI5CB	Phase 3 Trial	Chloroquine increases the expression of Lymphotoxin-beta (LTB).	[14]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Lymphotoxin-beta (LTB).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Lymphotoxin-beta (LTB).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Lymphotoxin-beta (LTB).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Lymphotoxin-beta (LTB).	[17]
PF-3758309	DM36PKZ	Phase 1	PF-3758309 increases the expression of Lymphotoxin-beta (LTB).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Lymphotoxin-beta (LTB).	[19]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Lymphotoxin-beta (LTB).	[20]

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] Human 3D multicellular microtissues: an upgraded model for the in vitro mechanistic investigation of inflammation-associated drug toxicity. Toxicol Lett. 2019 Sep 15;312:34-44.
• [3] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [4] Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells. Br J Pharmacol. 2013 May;169(1):167-78.
• [5] Prenatal arsenic exposure and shifts in the newborn proteome: interindividual differences in tumor necrosis factor (TNF)-responsive signaling. Toxicol Sci. 2014 Jun;139(2):328-37. doi: 10.1093/toxsci/kfu053. Epub 2014 Mar 27.
• [6] Improved apoptotic cell death in drug-resistant non-small-cell lung cancer cells by tumor necrosis factor-related apoptosis-inducing ligand-based treatment. J Pharmacol Exp Ther. 2014 Mar;348(3):360-71. doi: 10.1124/jpet.113.210054. Epub 2013 Dec 17.
• [7] Progesterone and calcitriol attenuate inflammatory cytokines CXCL1 and CXCL2 in ovarian and endometrial cancer cells. J Cell Biochem. 2012 Oct;113(10):3143-52. doi: 10.1002/jcb.24191.
• [8] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [9] Gene expression profile of human lymphoid CEM cells sensitive and resistant to glucocorticoid-evoked apoptosis. Genomics. 2003 Jun;81(6):543-55.
• [10] Effects of tobacco compounds on gene expression in fetal lung fibroblasts. Environ Toxicol. 2008 Aug;23(4):423-34.
• [11] Simvastatin inactivates beta1-integrin and extracellular signal-related kinase signaling and inhibits cell proliferation in head and neck squamous cell carcinoma cells. Cancer Sci. 2007 Jun;98(6):890-9.
• [12] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [13] Gene-expression profiling during curcumin-induced apoptosis reveals downregulation of CXCR4. Exp Hematol. 2007 Jan;35(1):84-95.
• [14] Reactive oxygen species mediate chloroquine-induced expression of chemokines by human astroglial cells. Glia. 2004 Jul;47(1):9-20. doi: 10.1002/glia.20017.
• [15] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [16] 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.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] 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.
• [19] 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.
• [20] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.