Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1MEZZN)

• DOT Name: TNF receptor-associated factor 2 (TRAF2)
• Synonyms: EC 2.3.2.27; E3 ubiquitin-protein ligase TRAF2; RING-type E3 ubiquitin transferase TRAF2; Tumor necrosis factor type 2 receptor-associated protein 3
• Gene Name: TRAF2
• Related Disease:
  B-cell neoplasm
  Lung adenocarcinoma
  Acute myelogenous leukaemia
  Adult glioblastoma
  Advanced cancer
  Alzheimer disease
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Cardiac failure
  Cerebral infarction
  Colon cancer
  Colon carcinoma
  Congestive heart failure
  Epithelial ovarian cancer
  Glioblastoma multiforme
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Inflammatory bowel disease
  Lung cancer
  Lung carcinoma
  Melanoma
  Metastatic prostate carcinoma
  Multiple sclerosis
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic cancer
  Parkinson disease
  Plasma cell myeloma
  Small lymphocytic lymphoma
  Stroke
  Arteriosclerosis
  Atherosclerosis
  Gastric cancer
  Head-neck squamous cell carcinoma
  Matthew-Wood syndrome
  Nasopharyngeal carcinoma
  Osteoarthritis
  Prostate cancer
  Prostate carcinoma
  Stomach cancer
  Asthma
  Glioma
  Liver cancer
  Lymphoma
  Metastatic malignant neoplasm
  Neuroblastoma
  Systemic lupus erythematosus
• UniProt ID: TRAF2_HUMAN
• PDB ID: 1CA4; 1CA9; 1CZY; 1CZZ; 1D00; 1D01; 1D0A; 1D0J; 1F3V; 1QSC; 3KNV; 3M06; 3M0A; 3M0D; 8T5Q
• EC Number: 2.3.2.27
• Pfam ID: PF21355 ; PF21341 ; PF16673 ; PF00097 ; PF02176
• Sequence:
  MAAASVTPPGSLELLQPGFSKTLLGTKLEAKYLCSACRNVLRRPFQAQCGHRYCSFCLAS
  ILSSGPQNCAACVHEGIYEEGISILESSSAFPDNAARREVESLPAVCPSDGCTWKGTLKE
  YESCHEGRCPLMLTECPACKGLVRLGEKERHLEHECPERSLSCRHCRAPCCGADVKAHHE
  VCPKFPLTCDGCGKKKIPREKFQDHVKTCGKCRVPCRFHAIGCLETVEGEKQQEHEVQWL
  REHLAMLLSSVLEAKPLLGDQSHAGSELLQRCESLEKKTATFENIVCVLNREVERVAMTA
  EACSRQHRLDQDKIEALSSKVQQLERSIGLKDLAMADLEQKVLEMEASTYDGVFIWKISD
  FARKRQEAVAGRIPAIFSPAFYTSRYGYKMCLRIYLNGDGTGRGTHLSLFFVVMKGPNDA
  LLRWPFNQKVTLMLLDQNNREHVIDAFRPDVTSSSFQRPVNDMNIASGCPLFCPVSKMEA
  KNSYVRDDAIFIKAIVDLTGL
• Function: Regulates activation of NF-kappa-B and JNK and plays a central role in the regulation of cell survival and apoptosis. Required for normal antibody isotype switching from IgM to IgG. Has E3 ubiquitin-protein ligase activity and promotes 'Lys-63'-linked ubiquitination of target proteins, such as BIRC3, RIPK1 and TICAM1. Is an essential constituent of several E3 ubiquitin-protein ligase complexes, where it promotes the ubiquitination of target proteins by bringing them into contact with other E3 ubiquitin ligases. Regulates BIRC2 and BIRC3 protein levels by inhibiting their autoubiquitination and subsequent degradation; this does not depend on the TRAF2 RING-type zinc finger domain. Plays a role in mediating activation of NF-kappa-B by EIF2AK2/PKR. In complex with BIRC2 or BIRC3, promotes ubiquitination of IKBKE.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  NF-kappa B sig.ling pathway (hsa04064)
  Sphingolipid sig.ling pathway (hsa04071)
  Mitophagy - animal (hsa04137)
  Protein processing in endoplasmic reticulum (hsa04141)
  Apoptosis (hsa04210)
  Necroptosis (hsa04217)
  Osteoclast differentiation (hsa04380)
  NOD-like receptor sig.ling pathway (hsa04621)
  RIG-I-like receptor sig.ling pathway (hsa04622)
  IL-17 sig.ling pathway (hsa04657)
  TNF sig.ling pathway (hsa04668)
  Adipocytokine sig.ling pathway (hsa04920)
  Non-alcoholic fatty liver disease (hsa04932)
  Alzheimer disease (hsa05010)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Spinocerebellar ataxia (hsa05017)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Yersinia infection (hsa05135)
  Hepatitis C (hsa05160)
  Human cytomegalovirus infection (hsa05163)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Human immunodeficiency virus 1 infection (hsa05170)
  Pathways in cancer (hsa05200)
  Viral carcinogenesis (hsa05203)
  Small cell lung cancer (hsa05222)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  Regulation by c-FLIP (R-HSA-3371378)
  RIPK1-mediated regulated necrosis (R-HSA-5213460)
  CASP8 activity is inhibited (R-HSA-5218900)
  TNFR1-induced proapoptotic signaling (R-HSA-5357786)
  Regulation of TNFR1 signaling (R-HSA-5357905)
  TNFR1-induced NF-kappa-B signaling pathway (R-HSA-5357956)
  TNFR2 non-canonical NF-kB pathway (R-HSA-5668541)
  Regulation of necroptotic cell death (R-HSA-5675482)
  TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway (R-HSA-5676594)
  Ub-specific processing proteases (R-HSA-5689880)
  Dimerization of procaspase-8 (R-HSA-69416)
  TNF signaling (R-HSA-75893)
  TRAF6 mediated IRF7 activation (R-HSA-933541)
  TRAF6 mediated NF-kB activation (R-HSA-933542)
  Defective RIPK1-mediated regulated necrosis (R-HSA-9693928)
  Regulation of NF-kappa B signaling (R-HSA-9758274)
  Caspase activation via Death Receptors in the presence of ligand (R-HSA-140534)

Molecular Interaction Atlas (MIA) of This DOT

49 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Definitive	Altered Expression	[1]
Lung adenocarcinoma	DISD51WR	Definitive	Altered Expression	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Alzheimer disease	DISF8S70	Strong	Biomarker	[6]
Bladder cancer	DISUHNM0	Strong	Biomarker	[7]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Cardiac failure	DISDC067	Strong	Genetic Variation	[8]
Cerebral infarction	DISR1WNP	Strong	Biomarker	[9]
Colon cancer	DISVC52G	Strong	Biomarker	[10]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[10]
Congestive heart failure	DIS32MEA	Strong	Genetic Variation	[8]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[11]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[4]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[12]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[13]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[14]
Lung cancer	DISCM4YA	Strong	Biomarker	[15]
Lung carcinoma	DISTR26C	Strong	Biomarker	[15]
Melanoma	DIS1RRCY	Strong	Altered Expression	[16]
Metastatic prostate carcinoma	DISVBEZ9	Strong	Altered Expression	[17]
Multiple sclerosis	DISB2WZI	Strong	Altered Expression	[18]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[19]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[11]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[11]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[20]
Parkinson disease	DISQVHKL	Strong	Biomarker	[21]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[22]
Small lymphocytic lymphoma	DIS30POX	Strong	Genetic Variation	[23]
Stroke	DISX6UHX	Strong	Biomarker	[9]
Arteriosclerosis	DISK5QGC	moderate	Altered Expression	[24]
Atherosclerosis	DISMN9J3	moderate	Altered Expression	[24]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[25]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Biomarker	[26]
Matthew-Wood syndrome	DISA7HR7	moderate	Altered Expression	[20]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Altered Expression	[27]
Osteoarthritis	DIS05URM	moderate	Altered Expression	[28]
Prostate cancer	DISF190Y	moderate	Altered Expression	[17]
Prostate carcinoma	DISMJPLE	moderate	Altered Expression	[17]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[25]
Asthma	DISW9QNS	Limited	Altered Expression	[29]
Glioma	DIS5RPEH	Limited	Altered Expression	[30]
Liver cancer	DISDE4BI	Limited	Biomarker	[31]
Lymphoma	DISN6V4S	Limited	Posttranslational Modification	[32]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[33]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[34]
Systemic lupus erythematosus	DISI1SZ7	Limited	Altered Expression	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Deoxycholic acid	DM3GYAL	Approved	TNF receptor-associated factor 2 (TRAF2) decreases the response to substance of Deoxycholic acid.	[55]
Ibrutinib	DMHZCPO	Approved	TNF receptor-associated factor 2 (TRAF2) decreases the response to substance of Ibrutinib.	[56]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of TNF receptor-associated factor 2 (TRAF2).	[35]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of TNF receptor-associated factor 2 (TRAF2).	[36]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of TNF receptor-associated factor 2 (TRAF2).	[37]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of TNF receptor-associated factor 2 (TRAF2).	[38]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of TNF receptor-associated factor 2 (TRAF2).	[39]
Quercetin	DM3NC4M	Approved	Quercetin affects the expression of TNF receptor-associated factor 2 (TRAF2).	[40]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of TNF receptor-associated factor 2 (TRAF2).	[41]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of TNF receptor-associated factor 2 (TRAF2).	[42]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of TNF receptor-associated factor 2 (TRAF2).	[43]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of TNF receptor-associated factor 2 (TRAF2).	[44]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the expression of TNF receptor-associated factor 2 (TRAF2).	[45]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of TNF receptor-associated factor 2 (TRAF2).	[46]
Ceritinib	DMB920Z	Approved	Ceritinib decreases the expression of TNF receptor-associated factor 2 (TRAF2).	[47]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of TNF receptor-associated factor 2 (TRAF2).	[48]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of TNF receptor-associated factor 2 (TRAF2).	[49]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of TNF receptor-associated factor 2 (TRAF2).	[51]
EMODIN	DMAEDQG	Terminated	EMODIN increases the expression of TNF receptor-associated factor 2 (TRAF2).	[52]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of TNF receptor-associated factor 2 (TRAF2).	[54]

2 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 decreases the methylation of TNF receptor-associated factor 2 (TRAF2).	[50]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of TNF receptor-associated factor 2 (TRAF2).	[53]

References

• [1] Expression of TNF-receptor associated factor 2 correlates with poor progression-free survival time in ABC-like primary nodal diffuse large B-cell lymphomas.Histopathology. 2008 Apr;52(5):578-84. doi: 10.1111/j.1365-2559.2008.02970.x. Epub 2008 Feb 23.
• [2] Growth inhibition and radiosensitization of glioblastoma and lung cancer cells by small interfering RNA silencing of tumor necrosis factor receptor-associated factor 2.Cancer Res. 2008 Sep 15;68(18):7570-8. doi: 10.1158/0008-5472.CAN-08-0632.
• [3] Characterization of ZC3H15 as a potential TRAF-2-interacting protein implicated in the NFB pathway and overexpressed in AML.Int J Oncol. 2013 Jul;43(1):246-54. doi: 10.3892/ijo.2013.1924. Epub 2013 Apr 29.
• [4] Prognostic Significance of TNFR-Associated Factor 1 and 2 (TRAF1 and TRAF2) in Glioblastoma.Med Sci Monit. 2017 Sep 19;23:4506-4512. doi: 10.12659/msm.903397.
• [5] TRAF2 Cooperates with Focal Adhesion Signaling to Regulate Cancer Cell Susceptibility to Anoikis.Mol Cancer Ther. 2019 Jan;18(1):139-146. doi: 10.1158/1535-7163.MCT-17-1261. Epub 2018 Oct 29.
• [6] TNFR-associated factor-2 (TRAF-2) in Alzheimer's disease.Neurobiol Aging. 2009 Jul;30(7):1052-60. doi: 10.1016/j.neurobiolaging.2007.10.014. Epub 2007 Dec 11.
• [7] IRE1-TRAF2-ASK1 complex-mediated endoplasmic reticulum stress and mitochondrial dysfunction contribute to CXC195-induced apoptosis in human bladder carcinoma T24 cells.Biochem Biophys Res Commun. 2015 May 8;460(3):530-6. doi: 10.1016/j.bbrc.2015.03.064. Epub 2015 Mar 19.
• [8] Cardioprotective Role of Tumor Necrosis Factor Receptor-Associated Factor 2 by Suppressing Apoptosis and Necroptosis.Circulation. 2017 Aug 22;136(8):729-742. doi: 10.1161/CIRCULATIONAHA.116.026240. Epub 2017 Jun 1.
• [9] TRAF2 protects against cerebral ischemia-induced brain injury by suppressing necroptosis.Cell Death Dis. 2019 Apr 15;10(5):328. doi: 10.1038/s41419-019-1558-5.
• [10] Tumor necrosis factor receptor-associated factor family protein 2 is a key mediator of the epidermal growth factor-induced ribosomal S6 kinase 2/cAMP-responsive element-binding protein/Fos protein signaling pathway.J Biol Chem. 2012 Jul 27;287(31):25881-92. doi: 10.1074/jbc.M112.359521. Epub 2012 Jun 8.
• [11] UCHL3 promotes ovarian cancer progression by stabilizing TRAF2 to activate the NF-B pathway.Oncogene. 2020 Jan;39(2):322-333. doi: 10.1038/s41388-019-0987-z. Epub 2019 Sep 2.
• [12] 1Hepatitis C virus NS5A protein modulates c-Jun N-terminal kinase through interaction with tumor necrosis factor receptor-associated factor 2.J Biol Chem. 2003 Aug 15;278(33):30711-8. doi: 10.1074/jbc.M209623200. Epub 2003 Jun 7.
• [13] Ischemia Induces Quiescence and Autophagy Dependence in Hepatocellular Carcinoma.Radiology. 2017 Jun;283(3):702-710. doi: 10.1148/radiol.2017160728. Epub 2017 Mar 2.
• [14] Gene expression of tumor necrosis factor receptor associated-factor (TRAF)-1 and TRAF-2 in inflammatory bowel disease.J Dig Dis. 2013 May;14(5):244-50. doi: 10.1111/1751-2980.12044.
• [15] Neuroplastin- mediates S100A8/A9-induced lung cancer disseminative progression.Mol Carcinog. 2019 Jun;58(6):980-995. doi: 10.1002/mc.22987. Epub 2019 Feb 27.
• [16] Expression of ring finger-deleted TRAF2 sensitizes metastatic melanoma cells to apoptosis via up-regulation of p38, TNFalpha and suppression of NF-kappaB activities.Oncogene. 2001 Apr 26;20(18):2243-53. doi: 10.1038/sj.onc.1204314.
• [17] TRAF2 is a Valuable Prognostic Biomarker in Patients with Prostate Cancer.Med Sci Monit. 2017 Aug 31;23:4192-4204. doi: 10.12659/msm.903500.
• [18] TRAF2 is upregulated in relapsing-remitting multiple sclerosis.Neuroimmunomodulation. 2013;20(3):177-83. doi: 10.1159/000346794. Epub 2013 Apr 5.
• [19] MicroRNA-647 promotes the therapeutic effectiveness of argon-helium cryoablation and inhibits cell proliferation through targeting TRAF2 via the NF-B signaling pathway in non-small cell lung cancer.Onco Targets Ther. 2018 Oct 10;11:6777-6784. doi: 10.2147/OTT.S159337. eCollection 2018.
• [20] TRAIL-induced expression of uPA and IL-8 strongly enhanced by overexpression of TRAF2 and Bcl-xL in pancreatic ductal adenocarcinoma cells.Hepatobiliary Pancreat Dis Int. 2013 Feb;12(1):94-8. doi: 10.1016/s1499-3872(13)60012-0.
• [21] Novel biomolecular information in rotenone-induced cellular model of Parkinson's disease.Gene. 2018 Mar 20;647:244-260. doi: 10.1016/j.gene.2018.01.023. Epub 2018 Jan 10.
• [22] Classical and/or alternative NF-kappaB pathway activation in multiple myeloma.Blood. 2010 Apr 29;115(17):3541-52. doi: 10.1182/blood-2009-09-243535. Epub 2010 Jan 6.
• [23] TNFR-associated factor 2 deficiency in B lymphocytes predisposes to chronic lymphocytic leukemia/small lymphocytic lymphoma in mice.J Immunol. 2012 Jul 15;189(2):1053-61. doi: 10.4049/jimmunol.1200814. Epub 2012 Jun 18.
• [24] Altered expression of TNFSF4 and TRAF2 mRNAs in peripheral blood mononuclear cells in patients with systemic lupus erythematosus: association with atherosclerotic symptoms and lupus nephritis.Inflamm Res. 2012 Dec;61(12):1347-54. doi: 10.1007/s00011-012-0535-6. Epub 2012 Jul 31.
• [25] EBV down-regulates COX-2 expression via TRAF2 and ERK signal pathway in EBV-associated gastric cancer.Virus Res. 2019 Oct 15;272:197735. doi: 10.1016/j.virusres.2019.197735. Epub 2019 Aug 29.
• [26] Tumor necrosis factor- triggers opposing signals in head and neck squamous cell carcinoma and induces apoptosis via mitochondrial- and non-mitochondrial-dependent pathways.Int J Oncol. 2019 Dec;55(6):1324-1338. doi: 10.3892/ijo.2019.4900. Epub 2019 Oct 17.
• [27] Constitutive activation of distinct NF-B signals in EBV-associated nasopharyngeal carcinoma.J Pathol. 2013 Nov;231(3):311-22. doi: 10.1002/path.4239. Epub 2013 Sep 3.
• [28] Up-regulation of TRAF2 inhibits chondrocytes apoptosis in lumbar facet joint osteoarthritis.Biochem Biophys Res Commun. 2018 Sep 10;503(3):1659-1665. doi: 10.1016/j.bbrc.2018.07.096. Epub 2018 Jul 25.
• [29] Apoptosis signals in atopy and asthma measured with cDNA arrays.Clin Exp Immunol. 2001 Feb;123(2):181-7. doi: 10.1046/j.1365-2249.2001.01441.x.
• [30] Expression of the tumor necrosis factor receptor-associated factors 1 and 2 and regulation of the nuclear factor-kappaB antiapoptotic activity in human gliomas.J Neurosurg. 2005 Nov;103(5):873-81. doi: 10.3171/jns.2005.103.5.0873.
• [31] RIPK1 Suppresses a TRAF2-Dependent Pathway to Liver Cancer.Cancer Cell. 2017 Jan 9;31(1):94-109. doi: 10.1016/j.ccell.2016.11.009. Epub 2016 Dec 22.
• [32] TRAF2 phosphorylation modulates tumor necrosis factor alpha-induced gene expression and cell resistance to apoptosis.Mol Cell Biol. 2009 Jan;29(2):303-14. doi: 10.1128/MCB.00699-08. Epub 2008 Nov 3.
• [33] High expression of tumor necrosis factor receptor-associated factor 2 promotes tumor metastasis and is associated with unfavorable prognosis in gastric cancer.J Gastroenterol Hepatol. 2018 Feb;33(2):431-442. doi: 10.1111/jgh.13818.
• [34] Ubiquitin ligase TRAF2 attenuates the transcriptional activity of the core clock protein BMAL1 and affects the maximal Per1 mRNA level of the circadian clock in cells.FEBS J. 2018 Aug;285(16):2987-3001. doi: 10.1111/febs.14595. Epub 2018 Jul 5.
• [35] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [36] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [37] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [38] 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.
• [39] 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.
• [40] Quercetin potentiates apoptosis by inhibiting nuclear factor-kappaB signaling in H460 lung cancer cells. Biol Pharm Bull. 2013;36(6):944-51. doi: 10.1248/bpb.b12-01004.
• [41] Arsenic trioxide induces different gene expression profiles of genes related to growth and apoptosis in glioma cells dependent on the p53 status. Mol Biol Rep. 2008 Sep;35(3):421-9.
• [42] Effect of zoledronic acid on oral fibroblasts and epithelial cells: a potential mechanism of bisphosphonate-associated osteonecrosis. Br J Haematol. 2009 Mar;144(5):667-76. doi: 10.1111/j.1365-2141.2008.07504.x. Epub 2008 Nov 20.
• [43] 5-Fluorouracil induces apoptosis through the suppression of NF-kappaB activity in human salivary gland cancer cells. Biochem Biophys Res Commun. 2000 Jul 14;273(3):1168-74. doi: 10.1006/bbrc.2000.3072.
• [44] 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.
• [45] Simvastatin potentiates TNF-alpha-induced apoptosis through the down-regulation of NF-kappaB-dependent antiapoptotic gene products: role of IkappaBalpha kinase and TGF-beta-activated kinase-1. J Immunol. 2007 Feb 15;178(4):2507-16. doi: 10.4049/jimmunol.178.4.2507.
• [46] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [47] 1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)-3-(2-(dimethylamino)ethyl)imidazolidin-2-one (ZX-42) inhibits cell proliferation and induces apoptosis via inhibiting ALK and its downstream pathways in Karpas299 cells. Toxicol Appl Pharmacol. 2022 Sep 1;450:116156. doi: 10.1016/j.taap.2022.116156. Epub 2022 Jul 6.
• [48] Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor-kappaB-regulated antiapoptotic and cell survival gene products in human multiple myeloma cells. Blood. 2007 Mar 15;109(6):2293-302. doi: 10.1182/blood-2006-02-003988. Epub 2006 Dec 12.
• [49] 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.
• [50] 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.
• [51] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [52] Gene expression alteration during redox-dependent enhancement of arsenic cytotoxicity by emodin in HeLa cells. Cell Res. 2005 Jul;15(7):511-22.
• [53] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [54] 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.
• [55] Development and molecular characterization of HCT-116 cell lines resistant to the tumor promoter and multiple stress-inducer, deoxycholate. Carcinogenesis. 2002 Dec;23(12):2063-80. doi: 10.1093/carcin/23.12.2063.
• [56] Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib. Blood. 2015 Sep 24;126(13):1565-74.