Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTLQ6S0)

• DOT Name: C-X-C motif chemokine 10 (CXCL10)
• Synonyms: 10 kDa interferon gamma-induced protein; Gamma-IP10; IP-10; Small-inducible cytokine B10
• Gene Name: CXCL10
• UniProt ID: CXL10_HUMAN
• PDB ID: 1LV9; 1O7Y; 1O7Z; 1O80; 8K2X
• Pfam ID: PF00048
• Sequence:
  MNQTAILICCLIFLTLSGIQGVPLSRTVRCTCISISNQPVNPRSLEKLEIIPASQFCPRV
  EIIATMKKKGEKRCLNPESKAIKNLLKAVSKERSKRSP
• Function: Pro-inflammatory cytokine that is involved in a wide variety of processes such as chemotaxis, differentiation, and activation of peripheral immune cells, regulation of cell growth, apoptosis and modulation of angiostatic effects. Plays thereby an important role during viral infections by stimulating the activation and migration of immune cells to the infected sites. Mechanistically, binding of CXCL10 to the CXCR3 receptor activates G protein-mediated signaling and results in downstream activation of phospholipase C-dependent pathway, an increase in intracellular calcium production and actin reorganization. In turn, recruitment of activated Th1 lymphocytes occurs at sites of inflammation. Activation of the CXCL10/CXCR3 axis also plays an important role in neurons in response to brain injury for activating microglia, the resident macrophage population of the central nervous system, and directing them to the lesion site. This recruitment is an essential element for neuronal reorganization.
• Tissue Specificity: Mainly secreted by monocytes, endothelial cells as well as fibroblasts. Expressed by epithelial cells in thymus . Microglial cells produce CXCL10 in response to viral stimulation .
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Viral protein interaction with cytokine and cytokine receptor (hsa04061)
  Chemokine sig.ling pathway (hsa04062)
  Toll-like receptor sig.ling pathway (hsa04620)
  RIG-I-like receptor sig.ling pathway (hsa04622)
  Cytosolic D.-sensing pathway (hsa04623)
  IL-17 sig.ling pathway (hsa04657)
  TNF sig.ling pathway (hsa04668)
  Hepatitis C (hsa05160)
  Influenza A (hsa05164)
  Epstein-Barr virus infection (hsa05169)
  Coro.virus disease - COVID-19 (hsa05171)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Interleukin-10 signaling (R-HSA-6783783)
  Chemokine receptors bind chemokines (R-HSA-380108)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Formoterol	DMSOURV	Approved	C-X-C motif chemokine 10 (CXCL10) increases the Eosinophilic disorders ADR of Formoterol.	[45]

43 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 C-X-C motif chemokine 10 (CXCL10).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of C-X-C motif chemokine 10 (CXCL10).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of C-X-C motif chemokine 10 (CXCL10).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of C-X-C motif chemokine 10 (CXCL10).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of C-X-C motif chemokine 10 (CXCL10).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of C-X-C motif chemokine 10 (CXCL10).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of C-X-C motif chemokine 10 (CXCL10).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of C-X-C motif chemokine 10 (CXCL10).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of C-X-C motif chemokine 10 (CXCL10).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of C-X-C motif chemokine 10 (CXCL10).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of C-X-C motif chemokine 10 (CXCL10).	[12]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of C-X-C motif chemokine 10 (CXCL10).	[7]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of C-X-C motif chemokine 10 (CXCL10).	[13]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of C-X-C motif chemokine 10 (CXCL10).	[14]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of C-X-C motif chemokine 10 (CXCL10).	[15]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of C-X-C motif chemokine 10 (CXCL10).	[16]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of C-X-C motif chemokine 10 (CXCL10).	[17]
Lucanthone	DMZLBUO	Approved	Lucanthone increases the expression of C-X-C motif chemokine 10 (CXCL10).	[20]
Methamphetamine	DMPM4SK	Approved	Methamphetamine increases the expression of C-X-C motif chemokine 10 (CXCL10).	[21]
Vitamin C	DMXJ7O8	Approved	Vitamin C increases the expression of C-X-C motif chemokine 10 (CXCL10).	[22]
Ritonavir	DMU764S	Approved	Ritonavir decreases the expression of C-X-C motif chemokine 10 (CXCL10).	[23]
Testosterone Undecanoate	DMZO10Y	Approved	Testosterone Undecanoate increases the expression of C-X-C motif chemokine 10 (CXCL10).	[25]
Tofacitinib	DMBS370	Approved	Tofacitinib decreases the expression of C-X-C motif chemokine 10 (CXCL10).	[27]
Hydroxychloroquine	DMSIVND	Approved	Hydroxychloroquine increases the expression of C-X-C motif chemokine 10 (CXCL10).	[28]
Amoxicillin	DMUYNEI	Approved	Amoxicillin decreases the expression of C-X-C motif chemokine 10 (CXCL10).	[29]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of C-X-C motif chemokine 10 (CXCL10).	[31]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of C-X-C motif chemokine 10 (CXCL10).	[8]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol decreases the expression of C-X-C motif chemokine 10 (CXCL10).	[32]
Jakafi	DMNORK8	Phase 3	Jakafi decreases the expression of C-X-C motif chemokine 10 (CXCL10).	[27]
Oxypurinol	DMURH4X	Phase 2/3	Oxypurinol increases the expression of C-X-C motif chemokine 10 (CXCL10).	[29]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of C-X-C motif chemokine 10 (CXCL10).	[33]
RGI-2001	DM4AC2F	Phase 2	RGI-2001 increases the expression of C-X-C motif chemokine 10 (CXCL10).	[34]
Calcium phosphate	DMGXCY9	Phase 2	Calcium phosphate increases the expression of C-X-C motif chemokine 10 (CXCL10).	[35]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of C-X-C motif chemokine 10 (CXCL10).	[37]
Celastrol	DMWQIJX	Preclinical	Celastrol increases the expression of C-X-C motif chemokine 10 (CXCL10).	[38]
Acteoside	DM0YHKB	Terminated	Acteoside decreases the expression of C-X-C motif chemokine 10 (CXCL10).	[8]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of C-X-C motif chemokine 10 (CXCL10).	[13]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of C-X-C motif chemokine 10 (CXCL10).	[40]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of C-X-C motif chemokine 10 (CXCL10).	[41]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of C-X-C motif chemokine 10 (CXCL10).	[42]
Bilirubin	DMI0V4O	Investigative	Bilirubin increases the expression of C-X-C motif chemokine 10 (CXCL10).	[43]
Rutin	DMEHRAJ	Investigative	Rutin decreases the expression of C-X-C motif chemokine 10 (CXCL10).	[8]
PD-168393	DMN8M5P	Investigative	PD-168393 increases the expression of C-X-C motif chemokine 10 (CXCL10).	[44]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Decitabine	DMQL8XJ	Approved	Decitabine affects the methylation of C-X-C motif chemokine 10 (CXCL10).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of C-X-C motif chemokine 10 (CXCL10).	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Clozapine	DMFC71L	Approved	Clozapine decreases the secretion of C-X-C motif chemokine 10 (CXCL10).	[18]
Cocaine	DMSOX7I	Approved	Cocaine increases the secretion of C-X-C motif chemokine 10 (CXCL10).	[19]
Nitric Oxide	DM1RBYG	Approved	Nitric Oxide decreases the secretion of C-X-C motif chemokine 10 (CXCL10).	[24]
Isoniazid	DM5JVS3	Approved	Isoniazid increases the secretion of C-X-C motif chemokine 10 (CXCL10).	[26]
Beclomethasone dipropionate	DM5NW1E	Phase 4	Beclomethasone dipropionate decreases the secretion of C-X-C motif chemokine 10 (CXCL10).	[30]
Doramapimod	DM6BU7N	Patented	Doramapimod decreases the secretion of C-X-C motif chemokine 10 (CXCL10).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the secretion of C-X-C motif chemokine 10 (CXCL10).	[39]
Nitrosoglutathione	DMZ9WI4	Investigative	Nitrosoglutathione decreases the secretion of C-X-C motif chemokine 10 (CXCL10).	[24]
ROLIPRAM	DMJ03UM	Investigative	ROLIPRAM decreases the secretion of C-X-C motif chemokine 10 (CXCL10).	[30]

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] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [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] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Recruitment of uterine NK cells: induction of CXC chemokine ligands 10 and 11 in human endometrium by estradiol and progesterone. J Immunol. 2004 Dec 1;173(11):6760-6. doi: 10.4049/jimmunol.173.11.6760.
• [8] Plant polyphenols differentially modulate inflammatory responses of human keratinocytes by interfering with activation of transcription factors NFB and AhR and EGFR-ERK pathway. Toxicol Appl Pharmacol. 2011 Sep 1;255(2):138-49.
• [9] 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.
• [10] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [11] Promoter methylation of PARG1, a novel candidate tumor suppressor gene in mantle-cell lymphomas. Haematologica. 2007 Apr;92(4):460-8. doi: 10.3324/haematol.10337.
• [12] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] 13-cis retinoic acid inhibits development and progression of chronic allograft nephropathy. Am J Pathol. 2005 Jul;167(1):285-98. doi: 10.1016/S0002-9440(10)62973-2.
• [15] Increased sensitivity for troglitazone-induced cytotoxicity using a human in vitro co-culture model. Toxicol In Vitro. 2009 Oct;23(7):1387-95.
• [16] Chemicals with weak skin sensitizing properties can be identified using low-density microarrays on immature dendritic cells. Toxicol Lett. 2007 Nov 1;174(1-3):98-109. doi: 10.1016/j.toxlet.2007.08.015. Epub 2007 Sep 5.
• [17] MEK/ERK dependent activation of STAT1 mediates dasatinib-induced differentiation of acute myeloid leukemia. PLoS One. 2013 Jun 25;8(6):e66915. doi: 10.1371/journal.pone.0066915. Print 2013.
• [18] Toxicoproteomics reveals an effect of clozapine on autophagy in human liver spheroids. Toxicol Mech Methods. 2023 Jun;33(5):401-410. doi: 10.1080/15376516.2022.2156005. Epub 2022 Dec 19.
• [19] Cocaine opens the blood-brain barrier to HIV-1 invasion. J Neurovirol. 1998 Dec;4(6):619-26. doi: 10.3109/13550289809114228.
• [20] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [21] Methamphetamine alters the normal progression by inducing cell cycle arrest in astrocytes. PLoS One. 2014 Oct 7;9(10):e109603.
• [22] Pharmacologic concentrations of ascorbic acid cause diverse influence on differential expressions of angiogenic chemokine genes in different hepatocellular carcinoma cell lines. Biomed Pharmacother. 2010 May;64(5):348-51. doi: 10.1016/j.biopha.2009.06.005. Epub 2009 Oct 22.
• [23] Transcriptional profiling suggests that Nevirapine and Ritonavir cause drug induced liver injury through distinct mechanisms in primary human hepatocytes. Chem Biol Interact. 2016 Aug 5;255:31-44.
• [24] Regulatory role of nitric oxide on monocyte-derived dendritic cell functions. J Interferon Cytokine Res. 2003 Aug;23(8):423-31. doi: 10.1089/107999003322277838.
• [25] Levonorgestrel enhances spermatogenesis suppression by testosterone with greater alteration in testicular gene expression in men. Biol Reprod. 2009 Mar;80(3):484-92.
• [26] Characterization of drug-specific signaling between primary human hepatocytes and immune cells. Toxicol Sci. 2017 Jul 1;158(1):76-89.
• [27] Regulation of inflammatory responses in tumor necrosis factor-activated and rheumatoid arthritis synovial macrophages by JAK inhibitors. Arthritis Rheum. 2012 Dec;64(12):3856-66. doi: 10.1002/art.37691.
• [28] Hydroxychloroquine-inhibited dengue virus is associated with host defense machinery. J Interferon Cytokine Res. 2015 Mar;35(3):143-56. doi: 10.1089/jir.2014.0038. Epub 2014 Oct 16.
• [29] Systemic drugs inducing non-immediate cutaneous adverse reactions and contact sensitizers evoke similar responses in THP-1 cells. J Appl Toxicol. 2015 Apr;35(4):398-406. doi: 10.1002/jat.3033. Epub 2014 Aug 4.
• [30] The role of IFN-gamma in regulation of IFN-gamma-inducible protein 10 (IP-10) expression in lung epithelial cell and peripheral blood mononuclear cell co-cultures. Respir Res. 2007 Nov 8;8(1):80. doi: 10.1186/1465-9921-8-80.
• [31] 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.
• [32] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [33] Upregulation of genes orchestrating keratinocyte differentiation, including the novel marker gene ID2, by contact sensitizers in human bulge-derived keratinocytes. J Biochem Mol Toxicol. 2010 Jan-Feb;24(1):10-20.
• [34] Sustained expansion of NKT cells and antigen-specific T cells after injection of alpha-galactosyl-ceramide loaded mature dendritic cells in cancer patients. J Exp Med. 2005 May 2;201(9):1503-17. doi: 10.1084/jem.20042592.
• [35] Human osteoclasts express different CXC chemokines depending on cell culture substrate: molecular and immunocytochemical evidence of high levels of CXCL10 and CXCL12. Histochem Cell Biol. 2003 Nov;120(5):391-400. doi: 10.1007/s00418-003-0587-3. Epub 2003 Nov 5.
• [36] 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.
• [37] Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16669-74. doi: 10.1073/pnas.1108190108. Epub 2011 Sep 26.
• [38] The quinone methide aurin is a heat shock response inducer that causes proteotoxic stress and Noxa-dependent apoptosis in malignant melanoma cells. J Biol Chem. 2015 Jan 16;290(3):1623-38.
• [39] Bisphenol A exposure alters release of immune and developmental modulators and expression of estrogen receptors in human fetal lung fibroblasts. J Environ Sci (China). 2016 Oct;48:11-23. doi: 10.1016/j.jes.2016.02.013. Epub 2016 Apr 29.
• [40] Effects of paraquat and capsaicin on the expression of genes related to inflammatory, immune responses and cell death in immortalized human HaCat keratinocytes. Int J Immunopathol Pharmacol. 2011 Oct-Dec;24(4):861-8.
• [41] Air pollution-related metals induce differential cytokine responses in bronchial epithelial cells. Toxicol In Vitro. 2016 Oct;36:53-65. doi: 10.1016/j.tiv.2016.07.004. Epub 2016 Jul 15.
• [42] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.
• [43] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.
• [44] Plant polyphenols regulate chemokine expression and tissue repair in human keratinocytes through interaction with cytoplasmic and nuclear components of epidermal growth factor receptor system. Antioxid Redox Signal. 2012 Feb 15;16(4):314-28. doi: 10.1089/ars.2011.4053. Epub 2011 Dec 1.
• [45] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.