Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD8DCBJ)

• DOT Name: Protein timeless homolog (TIMELESS)
• Synonyms: hTIM
• Gene Name: TIMELESS
• Related Disease:
  Allergic rhinitis
  Ebola virus infection
  Allergic asthma
  Arteriosclerosis
  Atherosclerosis
  Atrial fibrillation
  Autism spectrum disorder
  Autoimmune disease
  B-cell lymphoma
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Cardiac failure
  Cardiovascular disease
  Cervical cancer
  Cervical carcinoma
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Congestive heart failure
  Depression
  Dilated cardiomyopathy 1A
  Glioma
  Head and neck carcinoma
  Hepatitis A virus infection
  Hepatitis C virus infection
  Immune system disorder
  Major depressive disorder
  Mood disorder
  Non-small-cell lung cancer
  Ovarian cancer
  Pneumonia
  Pneumonitis
  Renal cell carcinoma
  Rheumatoid arthritis
  Sleep disorder
  Systemic sclerosis
  Tuberculosis
  Vascular purpura
  Lung carcinoma
  Small-cell lung cancer
  Arthritis
  Bipolar disorder
  Dengue
  Lung cancer
  Melanoma
  Nasopharyngeal carcinoma
• UniProt ID: TIM_HUMAN
• PDB ID: 4XHT; 4XHU; 4XHW; 5MQI; 6T9Q; 6TAZ; 7PFO; 7PLO; 8B9D
• Pfam ID: PF04821 ; PF05029
• Sequence:
  MDLHMMNCELLATCSALGYLEGDTYHKEPDCLESVKDLIRYLRHEDETRDVRQQLGAAQI
  LQSDLLPILTQHHQDKPLFDAVIRLMVNLTQPALLCFGNLPKEPSFRHHFLQVLTYLQAY
  KEAFASEKAFGVLSETLYELLQLGWEERQEEDNLLIERILLLVRNILHVPADLDQEKKID
  DDASAHDQLLWAIHLSGLDDLLLFLASSSAEEQWSLHVLEIVSLMFRDQNPEQLAGVGQG
  RLAQERSADFAELEVLRQREMAEKKTRALQRGNRHSRFGGSYIVQGLKSIGERDLIFHKG
  LHNLRNYSSDLGKQPKKVPKRRQAARELSIQRRSALNVRLFLRDFCSEFLENCYNRLMGS
  VKDHLLREKAQQHDETYYMWALAFFMAFNRAASFRPGLVSETLSVRTFHFIEQNLTNYYE
  MMLTDRKEAASWARRMHLALKAYQELLATVNEMDISPDEAVRESSRIIKNNIFYVMEYRE
  LFLALFRKFDERCQPRSFLRDLVETTHLFLKMLERFCRSRGNLVVQNKQKKRRKKKKKVL
  DQAIVSGNVPSSPEEVEAVWPALAEQLQCCAQNSELSMDSVVPFDAASEVPVEEQRAEAM
  VRIQDCLLAGQAPQALTLLRSAREVWPEGDVFGSQDISPEEEIQLLKQILSAPLPRQQGP
  EERGAEEEEEEEEEEEEELQVVQVSEKEFNFLDYLKRFACSTVVRAYVLLLRSYQQNSAH
  TNHCIVKMLHRLAHDLKMEALLFQLSVFCLFNRLLSDPAAGAYKELVTFAKYILGKFFAL
  AAVNQKAFVELLFWKNTAVVREMTEGYGSLDDRSSSRRAPTWSPEEEAHLRELYLANKDV
  EGQDVVEAILAHLNTVPRTRKQIIHHLVQMGLADSVKDFQRKGTHIVLWTGDQELELQRL
  FEEFRDSDDVLGHIMKNITAKRSRARIVDKLLALGLVAERRELYKKRQKKLASSILPNGA
  ESLKDFCQEDLEEEENLPEEDSEEEEEGGSEAEQVQGSLVLSNENLGQSLHQEGFSIPLL
  WLQNCLIRAADDREEDGCSQAVPLVPLTEENEEAMENEQFQQLLRKLGVRPPASGQETFW
  RIPAKLSPTQLRRAAASLSQPEEEQKLQPELQPKVPGEQGSDEEHCKEHRAQALRALLLA
  HKKKAGLASPEEEDAVGKEPLKAAPKKRQLLDSDEEQEEDEGRNRAPELGAPGIQKKKRY
  QIEDDEDD
• Function: Plays an important role in the control of DNA replication, maintenance of replication fork stability, maintenance of genome stability throughout normal DNA replication, DNA repair and in the regulation of the circadian clock. Required to stabilize replication forks during DNA replication by forming a complex with TIPIN: this complex regulates DNA replication processes under both normal and stress conditions, stabilizes replication forks and influences both CHEK1 phosphorylation and the intra-S phase checkpoint in response to genotoxic stress. During DNA replication, inhibits the CMG complex ATPase activity and activates DNA polymerases catalytic activities, coupling DNA unwinding and DNA synthesis. TIMELESS promotes TIPIN nuclear localization. Plays a role in maintaining processive DNA replication past genomic guanine-rich DNA sequences that form G-quadruplex (G4) structures, possibly together with DDX1. Involved in cell survival after DNA damage or replication stress by promoting DNA repair. In response to double-strand breaks (DSBs), accumulates at DNA damage sites and promotes homologous recombination repair via its interaction with PARP1. May be specifically required for the ATR-CHEK1 pathway in the replication checkpoint induced by hydroxyurea or ultraviolet light. Involved in the determination of period length and in the DNA damage-dependent phase advancing of the circadian clock. Negatively regulates CLOCK|NPAS2-ARTNL/BMAL1|ARTNL2/BMAL2-induced transactivation of PER1 possibly via translocation of PER1 into the nucleus. May play a role as destabilizer of the PER2-CRY2 complex. May also play an important role in epithelial cell morphogenesis and formation of branching tubules.
• Tissue Specificity: Expressed in all tissues examined including brain, heart, lung, liver, skeletal muscle, kidney, placenta, pancreas, spleen, thymus and testis. Highest levels of expression in placenta, pancreas, thymus and testis.
• Reactome Pathway: Processing of DNA double-strand break ends (R-HSA-5693607)

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Allergic rhinitis	DIS3U9HN	Definitive	Biomarker	[1]
Ebola virus infection	DISJAVM1	Definitive	Biomarker	[2]
Allergic asthma	DISHF0H3	Strong	Genetic Variation	[3]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[4]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[4]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[5]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[6]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[7]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[8]
Brain neoplasm	DISY3EKS	Strong	Altered Expression	[9]
Breast cancer	DIS7DPX1	Strong	Biomarker	[10]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[10]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[11]
Cardiac failure	DISDC067	Strong	Biomarker	[12]
Cardiovascular disease	DIS2IQDX	Strong	Altered Expression	[13]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[14]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[14]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[15]
Colon cancer	DISVC52G	Strong	Biomarker	[16]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[16]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[12]
Depression	DIS3XJ69	Strong	Biomarker	[17]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Genetic Variation	[18]
Glioma	DIS5RPEH	Strong	Altered Expression	[19]
Head and neck carcinoma	DISOU1DS	Strong	Biomarker	[20]
Hepatitis A virus infection	DISUMFQV	Strong	Biomarker	[21]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[22]
Immune system disorder	DISAEGPH	Strong	Genetic Variation	[18]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[23]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[23]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[24]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[15]
Pneumonia	DIS8EF3M	Strong	Biomarker	[25]
Pneumonitis	DIS88E0K	Strong	Biomarker	[25]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[15]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[26]
Sleep disorder	DIS3JP1U	Strong	Genetic Variation	[27]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[28]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[29]
Vascular purpura	DIS6ZZMF	Strong	Altered Expression	[30]
Lung carcinoma	DISTR26C	moderate	Altered Expression	[24]
Small-cell lung cancer	DISK3LZD	moderate	Altered Expression	[31]
Arthritis	DIST1YEL	Limited	Biomarker	[32]
Bipolar disorder	DISAM7J2	Limited	Genetic Variation	[23]
Dengue	DISKH221	Limited	Biomarker	[33]
Lung cancer	DISCM4YA	Limited	Altered Expression	[24]
Melanoma	DIS1RRCY	Limited	Biomarker	[34]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[35]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Protein timeless homolog (TIMELESS) affects the response to substance of Fluorouracil.	[60]

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 Protein timeless homolog (TIMELESS).	[36]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein timeless homolog (TIMELESS).	[37]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein timeless homolog (TIMELESS).	[38]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein timeless homolog (TIMELESS).	[39]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein timeless homolog (TIMELESS).	[40]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein timeless homolog (TIMELESS).	[41]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein timeless homolog (TIMELESS).	[42]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Protein timeless homolog (TIMELESS).	[43]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Protein timeless homolog (TIMELESS).	[44]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Protein timeless homolog (TIMELESS).	[45]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Protein timeless homolog (TIMELESS).	[46]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Protein timeless homolog (TIMELESS).	[47]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Protein timeless homolog (TIMELESS).	[48]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Protein timeless homolog (TIMELESS).	[49]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Protein timeless homolog (TIMELESS).	[50]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protein timeless homolog (TIMELESS).	[51]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Protein timeless homolog (TIMELESS).	[52]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of Protein timeless homolog (TIMELESS).	[53]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein timeless homolog (TIMELESS).	[55]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Protein timeless homolog (TIMELESS).	[57]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Protein timeless homolog (TIMELESS).	[52]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of Protein timeless homolog (TIMELESS).	[58]
Microcystin-LR	DMTMLRN	Investigative	Microcystin-LR decreases the expression of Protein timeless homolog (TIMELESS).	[59]

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 affects the methylation of Protein timeless homolog (TIMELESS).	[54]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Protein timeless homolog (TIMELESS).	[56]

References

• [1] The T-cell immunoglobulin and mucin domain (Tim) gene family in asthma, allergy, and autoimmunity.Allergy Asthma Proc. 2013 Jan-Feb;34(1):e21-6. doi: 10.2500/aap.2013.34.3646.
• [2] Biomechanical characterization of TIM protein-mediated Ebola virus-host cell adhesion.Sci Rep. 2019 Jan 22;9(1):267. doi: 10.1038/s41598-018-36449-2.
• [3] Association analysis of -416G>C polymorphism of T-cell immunoglobulin and mucin domain-1 gene with asthma in Iran.Int J Immunogenet. 2015 Aug;42(4):265-9. doi: 10.1111/iji.12209. Epub 2015 Jun 3.
• [4] Anti-TIM-1 Monoclonal Antibody (RMT1-10) Attenuates Atherosclerosis By Expanding IgM-producing B1a Cells.J Am Heart Assoc. 2018 Jun 23;7(13):e008447. doi: 10.1161/JAHA.117.008447.
• [5] Discovery of new biomarkers for atrial fibrillation using a custom-made proteomics chip.Heart. 2017 Mar;103(5):377-382. doi: 10.1136/heartjnl-2016-309764. Epub 2016 Sep 8.
• [6] Dysregulation of T cell immunoglobulin and mucin domain 3 (TIM-3) signaling in peripheral immune cells is associated with immune dysfunction in autistic children.Mol Immunol. 2019 Feb;106:77-86. doi: 10.1016/j.molimm.2018.12.020. Epub 2018 Dec 24.
• [7] Association between T-Cell Immunoglobulin and Mucin Domain 3 (TIM-3) Genetic Polymorphisms and Susceptibility to Autoimmune Diseases.Immunol Invest. 2019 Aug;48(6):563-576. doi: 10.1080/08820139.2019.1599009. Epub 2019 May 2.
• [8] Expression of Tim-1 in primary CNS lymphoma.Cancer Med. 2016 Nov;5(11):3235-3245. doi: 10.1002/cam4.930. Epub 2016 Oct 5.
• [9] GRP78/BiP/HSPA5/Dna K is a universal therapeutic target for human disease.J Cell Physiol. 2015 Jul;230(7):1661-76. doi: 10.1002/jcp.24919.
• [10] Circadian gene variants and breast cancer.Cancer Lett. 2017 Apr 1;390:137-145. doi: 10.1016/j.canlet.2017.01.012. Epub 2017 Jan 18.
• [11] Oligonucleotide microarray analysis of estrogen receptor alpha-positive postmenopausal breast carcinomas: identification of HRPAP20 and TIMELESS as outstanding candidate markers to predict the response to tamoxifen.J Mol Endocrinol. 2007 Oct;39(4):305-18. doi: 10.1677/JME-07-0001.
• [12] Biomarker guidance allows a more personalized allocation of patients for remote patient management in heart failure: results from the TIM-HF2 trial.Eur J Heart Fail. 2019 Nov;21(11):1445-1458. doi: 10.1002/ejhf.1530. Epub 2019 Jun 17.
• [13] Proteomic Profiling for Cardiovascular Biomarker Discovery in Orthostatic Hypotension.Hypertension. 2018 Mar;71(3):465-472. doi: 10.1161/HYPERTENSIONAHA.117.10365. Epub 2018 Jan 2.
• [14] Aberrant TIMELESS expression is associated with poor clinical survival and lymph node metastasis in early-stage cervical carcinoma.Int J Oncol. 2017 Jan;50(1):173-184. doi: 10.3892/ijo.2016.3784. Epub 2016 Nov 29.
• [15] Development of a Novel Antibody-Drug Conjugate for the Potential Treatment of Ovarian, Lung, and Renal Cell Carcinoma Expressing TIM-1.Mol Cancer Ther. 2016 Dec;15(12):2946-2954. doi: 10.1158/1535-7163.MCT-16-0393. Epub 2016 Sep 26.
• [16] Activation of TIM1 induces colon cancer cell apoptosis via modulating Fas ligand expression.Biochem Biophys Res Commun. 2016 Apr 29;473(2):377-81. doi: 10.1016/j.bbrc.2016.02.085. Epub 2016 Feb 26.
• [17] Systematic analysis of circadian genes in a population-based sample reveals association of TIMELESS with depression and sleep disturbance.PLoS One. 2010 Feb 18;5(2):e9259. doi: 10.1371/journal.pone.0009259.
• [18] Associations Between TIM1 Polymorphisms and Dilated Cardiomyopathy in a Han Chinese Population.Int Heart J. 2016 Dec 2;57(6):742-746. doi: 10.1536/ihj.16-119. Epub 2016 Nov 4.
• [19] The analysis of deregulated expression of the timeless genes in gliomas.J Cancer Res Ther. 2018 Sep;14(Supplement):S708-S712. doi: 10.4103/0973-1482.187382.
• [20] Increased PD-1(+) and TIM-3(+) TILs during Cetuximab Therapy Inversely Correlate with Response in Head and Neck Cancer Patients.Cancer Immunol Res. 2017 May;5(5):408-416. doi: 10.1158/2326-6066.CIR-16-0333. Epub 2017 Apr 13.
• [21] Exosomes Exploit the Virus Entry Machinery and Pathway To Transmit Alpha Interferon-Induced Antiviral Activity.J Virol. 2018 Nov 27;92(24):e01578-18. doi: 10.1128/JVI.01578-18. Print 2018 Dec 15.
• [22] TIM-1 Promotes Hepatitis C Virus Cell Attachment and Infection.J Virol. 2017 Jan 3;91(2):e01583-16. doi: 10.1128/JVI.01583-16. Print 2017 Jan 15.
• [23] Significant role of gene-gene interactions of clock genes in mood disorder.J Affect Disord. 2019 Oct 1;257:510-517. doi: 10.1016/j.jad.2019.06.056. Epub 2019 Jul 2.
• [24] Prognostic value of TIM-1 expression in human non-small-cell lung cancer.J Transl Med. 2019 May 28;17(1):178. doi: 10.1186/s12967-019-1931-2.
• [25] Tim1 and Tim3 are not essential for experimental allergic asthma.Clin Exp Allergy. 2011 Jul;41(7):1012-21. doi: 10.1111/j.1365-2222.2011.03728.x. Epub 2011 Apr 7.
• [26] TIM family gene polymorphism and susceptibility to rheumatoid arthritis: Systematic review and meta-analysis.PLoS One. 2019 Feb 7;14(2):e0211146. doi: 10.1371/journal.pone.0211146. eCollection 2019.
• [27] Circadian-relevant genes are highly polymorphic in autism spectrum disorder patients.Brain Dev. 2016 Jan;38(1):91-9. doi: 10.1016/j.braindev.2015.04.006. Epub 2015 May 6.
• [28] TIM-1 defines a human regulatory B cell population that is altered in frequency and function in systemic sclerosis patients.Arthritis Res Ther. 2017 Jan 19;19(1):8. doi: 10.1186/s13075-016-1213-9.
• [29] Crystal structure of the apurinic/apyrimidinic endonuclease IV from Mycobacterium tuberculosis.Biochem Biophys Res Commun. 2018 Mar 25;498(1):111-118. doi: 10.1016/j.bbrc.2018.02.181. Epub 2018 Feb 27.
• [30] Decreased TIM-3 mRNA expression in peripheral blood mononuclear cells from nephropathy patients.Genet Mol Res. 2015 Jun 12;14(2):6543-8. doi: 10.4238/2015.June.12.7.
• [31] TIMELESS is overexpressed in lung cancer and its expression correlates with poor patient survival.Cancer Sci. 2013 Feb;104(2):171-7. doi: 10.1111/cas.12068. Epub 2013 Jan 7.
• [32] Inhibition of in vitro and in vivo T cell responses by recombinant human Tim-1 extracellular domain proteins.Int Immunol. 2006 Mar;18(3):473-84. doi: 10.1093/intimm/dxh388. Epub 2006 Feb 15.
• [33] TIM-1 As a Signal Receptor Triggers Dengue Virus-Induced Autophagy.Int J Mol Sci. 2019 Oct 2;20(19):4893. doi: 10.3390/ijms20194893.
• [34] TIM-4 Identifies IFN--Expressing Proinflammatory B Effector 1 Cells That Promote Tumor and Allograft Rejection.J Immunol. 2017 Oct 1;199(7):2585-2595. doi: 10.4049/jimmunol.1602107. Epub 2017 Aug 28.
• [35] TIMELESS confers cisplatin resistance in nasopharyngeal carcinoma by activating the Wnt/-catenin signaling pathway and promoting the epithelial mesenchymal transition.Cancer Lett. 2017 Aug 28;402:117-130. doi: 10.1016/j.canlet.2017.05.022. Epub 2017 Jun 3.
• [36] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [37] 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.
• [38] 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.
• [39] 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.
• [40] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [41] 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.
• [42] Bisphenol-A and estradiol exert novel gene regulation in human MCF-7 derived breast cancer cells. Mol Cell Endocrinol. 2004 Jun 30;221(1-2):47-55. doi: 10.1016/j.mce.2004.04.010.
• [43] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [44] 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.
• [45] 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.
• [46] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [47] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [48] mTOR inhibition reverses acquired endocrine therapy resistance of breast cancer cells at the cell proliferation and gene-expression levels. Cancer Sci. 2008 Oct;99(10):1992-2003. doi: 10.1111/j.1349-7006.2008.00955.x.
• [49] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [50] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [51] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [52] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [53] Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
• [54] 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.
• [55] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [56] 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.
• [57] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [58] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [59] Microcystin-LR-induced nuclear translocation of cGAS promotes mutagenesis in human hepatocytes by impeding homologous recombination repair. Toxicol Lett. 2023 Jan 15;373:94-104. doi: 10.1016/j.toxlet.2022.11.015. Epub 2022 Nov 23.
• [60] Mechanistic and predictive profiling of 5-Fluorouracil resistance in human cancer cells. Cancer Res. 2004 Nov 15;64(22):8167-76. doi: 10.1158/0008-5472.CAN-04-0970.