Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUC3S76)

• DOT Name: Lymphotoxin-alpha (LTA)
• Synonyms: LT-alpha; TNF-beta; Tumor necrosis factor ligand superfamily member 1
• Gene Name: LTA
• UniProt ID: TNFB_HUMAN
• PDB ID: 1TNR; 4MXV; 4MXW
• Pfam ID: PF00229
• Sequence:
  MTPPERLFLPRVCGTTLHLLLLGLLLVLLPGAQGLPGVGLTPSAAQTARQHPKMHLAHST
  LKPAAHLIGDPSKQNSLLWRANTDRAFLQDGFSLSNNSLLVPTSGIYFVYSQVVFSGKAY
  SPKATSSPLYLAHEVQLFSSQYPFHVPLLSSQKMVYPGLQEPWLHSMYHGAAFQLTQGDQ
  LSTHTDGIPHLVLSPSTVFFGAFAL
• Function: Cytokine that in its homotrimeric form binds to TNFRSF1A/TNFR1, TNFRSF1B/TNFBR and TNFRSF14/HVEM. In its heterotrimeric form with LTB binds to TNFRSF3/LTBR. Lymphotoxin is produced by lymphocytes and is cytotoxic for a wide range of tumor cells in vitro and in vivo.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Viral protein interaction with cytokine and cytokine receptor (hsa04061)
  NF-kappa B sig.ling pathway (hsa04064)
  TNF sig.ling pathway (hsa04668)
  Type I diabetes mellitus (hsa04940)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Herpes simplex virus 1 infection (hsa05168)
• Reactome Pathway:
  TNFs bind their physiological receptors (R-HSA-5669034)
  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

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Aspirin	DM672AH	Approved	Lymphotoxin-alpha (LTA) affects the response to substance of Aspirin.	[15]
Ibuprofen	DM8VCBE	Approved	Lymphotoxin-alpha (LTA) affects the response to substance of Ibuprofen.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of Lymphotoxin-alpha (LTA).	[1]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Lymphotoxin-alpha (LTA).	[2]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Lymphotoxin-alpha (LTA).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Lymphotoxin-alpha (LTA).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Lymphotoxin-alpha (LTA).	[5]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Lymphotoxin-alpha (LTA).	[6]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Lymphotoxin-alpha (LTA).	[7]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of Lymphotoxin-alpha (LTA).	[8]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Lymphotoxin-alpha (LTA).	[9]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Lymphotoxin-alpha (LTA).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Lymphotoxin-alpha (LTA).	[12]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Lymphotoxin-alpha (LTA).	[13]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the expression of Lymphotoxin-alpha (LTA).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Lymphotoxin-alpha (LTA).	[11]

References

• [1] 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.
• [2] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [3] 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.
• [4] 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.
• [5] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [6] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [7] Increased sensitivity for troglitazone-induced cytotoxicity using a human in vitro co-culture model. Toxicol In Vitro. 2009 Oct;23(7):1387-95.
• [8] Metronomic gemcitabine suppresses tumour growth, improves perfusion, and reduces hypoxia in human pancreatic ductal adenocarcinoma. Br J Cancer. 2010 Jun 29;103(1):52-60.
• [9] Grape resveratrol increases serum adiponectin and downregulates inflammatory genes in peripheral blood mononuclear cells: a triple-blind, placebo-controlled, one-year clinical trial in patients with stable coronary artery disease. Cardiovasc Drugs Ther. 2013 Feb;27(1):37-48. doi: 10.1007/s10557-012-6427-8.
• [10] 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.
• [11] 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.
• [12] Global gene expression analysis reveals novel transcription factors associated with long-term low-level exposure of EA.hy926 human endothelial cells to bisphenol A. Chem Biol Interact. 2023 Aug 25;381:110571. doi: 10.1016/j.cbi.2023.110571. Epub 2023 May 25.
• [13] 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.
• [14] The cinnamon-derived Michael acceptor cinnamic aldehyde impairs melanoma cell proliferation, invasiveness, and tumor growth. Free Radic Biol Med. 2009 Jan 15;46(2):220-31.
• [15] Nonsteroidal antiinflammatory drugs and decreased risk of advanced prostate cancer: modification by lymphotoxin alpha. Am J Epidemiol. 2006 Nov 15;164(10):984-9. doi: 10.1093/aje/kwj294. Epub 2006 Aug 24.