Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHB2AL1)

• DOT Name: CD70 antigen (CD70)
• Synonyms: CD27 ligand; CD27-L; Tumor necrosis factor ligand superfamily member 7; CD antigen CD70
• Gene Name: CD70
• Related Disease: Severe combined immunodeficiency due to CD70 deficiency
• UniProt ID: CD70_HUMAN
• PDB ID: 7KX0
• Pfam ID: PF00229
• Sequence:
  MPEEGSGCSVRRRPYGCVLRAALVPLVAGLVICLVVCIQRFAQAQQQLPLESLGWDVAEL
  QLNHTGPQQDPRLYWQGGPALGRSFLHGPELDKGQLRIHRDGIYMVHIQVTLAICSSTTA
  SRHHPTTLAVGICSPASRSISLLRLSFHQGCTIASQRLTPLARGDTLCTNLTGTLLPSRN
  TDETFFGVQWVRP
• Function: Cytokine which is the ligand for CD27. The CD70-CD27 pathway plays an important role in the generation and maintenance of T cell immunity, in particular during antiviral responses. Upon CD27 binding, induces the proliferation of costimulated T-cells and enhances the generation of cytolytic T-cells.
• KEGG Pathway: Cytokine-cytokine receptor interaction (hsa04060)
• Reactome Pathway: TNFs bind their physiological receptors (R-HSA-5669034)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Severe combined immunodeficiency due to CD70 deficiency	DISVOE09	Strong	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of CD70 antigen (CD70).	[2]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of CD70 antigen (CD70).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of CD70 antigen (CD70).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of CD70 antigen (CD70).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of CD70 antigen (CD70).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of CD70 antigen (CD70).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of CD70 antigen (CD70).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of CD70 antigen (CD70).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of CD70 antigen (CD70).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of CD70 antigen (CD70).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of CD70 antigen (CD70).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of CD70 antigen (CD70).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of CD70 antigen (CD70).	[7]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of CD70 antigen (CD70).	[13]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of CD70 antigen (CD70).	[14]
Menthol	DMG2KW7	Approved	Menthol increases the expression of CD70 antigen (CD70).	[15]
Vemurafenib	DM62UG5	Approved	Vemurafenib decreases the expression of CD70 antigen (CD70).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of CD70 antigen (CD70).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of CD70 antigen (CD70).	[19]
PF-3758309	DM36PKZ	Phase 1	PF-3758309 increases the expression of CD70 antigen (CD70).	[20]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of CD70 antigen (CD70).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of CD70 antigen (CD70).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of CD70 antigen (CD70).	[23]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of CD70 antigen (CD70).	[24]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of CD70 antigen (CD70).	[25]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of CD70 antigen (CD70).	[26]
U0126	DM31OGF	Investigative	U0126 decreases the expression of CD70 antigen (CD70).	[16]
PD98059	DMZC90M	Investigative	PD98059 decreases the expression of CD70 antigen (CD70).	[16]

References

• [1] Inherited CD70 deficiency in humans reveals a critical role for the CD70-CD27 pathway in immunity to Epstein-Barr virus infection. J Exp Med. 2017 Jan;214(1):73-89. doi: 10.1084/jem.20160784. Epub 2016 Dec 23.
• [2] 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.
• [3] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [4] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [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] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [8] 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.
• [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] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [12] 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.
• [13] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [14] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [15] 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.
• [16] Melanoma Expressed-CD70 Is Regulated by RhoA and MAPK Pathways without Affecting Vemurafenib Treatment Activity. PLoS One. 2016 Feb 1;11(2):e0148095. doi: 10.1371/journal.pone.0148095. eCollection 2016.
• [17] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [18] 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.
• [19] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [20] 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.
• [21] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [22] Genome-wide expression changes induced by bisphenol A, F and S in human stem cell derived hepatocyte-like cells. EXCLI J. 2020 Nov 4;19:1459-1476. doi: 10.17179/excli2020-2934. eCollection 2020.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [25] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [26] 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.