Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKPWB7Q)

• DOT Name: Apoptosis-inducing factor 1, mitochondrial (AIFM1)
• Synonyms: EC 1.6.99.-; Programmed cell death protein 8
• Gene Name: AIFM1
• Related Disease:
  Acute myelogenous leukaemia
  X-linked hereditary sensory and autonomic neuropathy with hearing loss
  Adult glioblastoma
  Autism spectrum disorder
  Breast cancer
  Cerebellar ataxia
  Cervical cancer
  Cervical carcinoma
  Charcot marie tooth disease
  Charcot-Marie-Tooth disease type 2
  Charcot-Marie-Tooth disease X-linked recessive 4
  Colon carcinoma
  Colorectal carcinoma
  Diabetic kidney disease
  Epilepsy
  Esophageal squamous cell carcinoma
  Glioblastoma multiforme
  Glioma
  Intellectual disability
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Melanoma
  Mitochondrial complex I deficiency
  Mitochondrial disease
  Mitochondrial encephalomyopathy
  Myopathy
  Neuronopathy, distal hereditary motor, type 5
  Peripheral sensory neuropathies
  Polyneuropathy
  Prostate neoplasm
  Retinitis pigmentosa
  Retinitis pigmentosa 1
  Severe X-linked mitochondrial encephalomyopathy
  Spondyloepimetaphyseal dysplasia, Bieganski type
  Stroke
  Breast carcinoma
  Hepatocellular carcinoma
  Juvenile Huntington disease
  Leigh syndrome
  Auditory neuropathy
  Parkinson disease
  Asthma
  Huntington disease
  Type-1 diabetes
• UniProt ID: AIFM1_HUMAN
• PDB ID: 1M6I; 4BUR; 4BV6; 4FDC; 4LII; 5FMH; 5FS6; 5FS7; 5FS8; 5FS9; 5KVH; 5KVI; 8D3E; 8D3G; 8D3H; 8D3I; 8D3J; 8D3K; 8D3N; 8D3O
• EC Number: 1.6.99.-
• Pfam ID: PF14721 ; PF07992
• Sequence:
  MFRCGGLAAGALKQKLVPLVRTVCVRSPRQRNRLPGNLFQRWHVPLELQMTRQMASSGAS
  GGKIDNSVLVLIVGLSTVGAGAYAYKTMKEDEKRYNERISGLGLTPEQKQKKAALSASEG
  EEVPQDKAPSHVPFLLIGGGTAAFAAARSIRARDPGARVLIVSEDPELPYMRPPLSKELW
  FSDDPNVTKTLRFKQWNGKERSIYFQPPSFYVSAQDLPHIENGGVAVLTGKKVVQLDVRD
  NMVKLNDGSQITYEKCLIATGGTPRSLSAIDRAGAEVKSRTTLFRKIGDFRSLEKISREV
  KSITIIGGGFLGSELACALGRKARALGTEVIQLFPEKGNMGKILPEYLSNWTMEKVRREG
  VKVMPNAIVQSVGVSSGKLLIKLKDGRKVETDHIVAAVGLEPNVELAKTGGLEIDSDFGG
  FRVNAELQARSNIWVAGDAACFYDIKLGRRRVEHHDHAVVSGRLAGENMTGAAKPYWHQS
  MFWSDLGPDVGYEAIGLVDSSLPTVGVFAKATAQDNPKSATEQSGTGIRSESETESEASE
  ITIPPSTPAVPQAPVQGEDYGKGVIFYLRDKVVVGIVLWNIFNRMPIARKIIKDGEQHED
  LNEVAKLFNIHED
• Function: Functions both as NADH oxidoreductase and as regulator of apoptosis. In response to apoptotic stimuli, it is released from the mitochondrion intermembrane space into the cytosol and to the nucleus, where it functions as a proapoptotic factor in a caspase-independent pathway. Release into the cytoplasm is mediated upon binding to poly-ADP-ribose chains. The soluble form (AIFsol) found in the nucleus induces 'parthanatos' i.e. caspase-independent fragmentation of chromosomal DNA. Binds to DNA in a sequence-independent manner. Interacts with EIF3G, and thereby inhibits the EIF3 machinery and protein synthesis, and activates caspase-7 to amplify apoptosis. Plays a critical role in caspase-independent, pyknotic cell death in hydrogen peroxide-exposed cells. In contrast, participates in normal mitochondrial metabolism. Plays an important role in the regulation of respiratory chain biogenesis by interacting with CHCHD4 and controlling CHCHD4 mitochondrial import ; [Isoform 4]: Has NADH oxidoreductase activity. Does not induce nuclear apoptosis; [Isoform 5]: Pro-apoptotic isoform.
• Tissue Specificity: Expressed in all tested tissues . Detected in muscle and skin fibroblasts (at protein level) . Expressed in osteoblasts (at protein level) .; [Isoform 3]: Brain specific.; [Isoform 4]: Expressed in all tested tissues except brain.; [Isoform 5]: Isoform 5 is frequently down-regulated in human cancers.
• KEGG Pathway:
  Apoptosis (hsa04210)
  Necroptosis (hsa04217)
• BioCyc Pathway: MetaCyc:ENSG00000156709-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

45 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Biomarker	[1]
X-linked hereditary sensory and autonomic neuropathy with hearing loss	DISHBBEM	Definitive	X-linked	[2]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[3]
Autism spectrum disorder	DISXK8NV	Strong	Altered Expression	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[6]
Cervical cancer	DISFSHPF	Strong	Biomarker	[7]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[7]
Charcot marie tooth disease	DIS3BT2L	Strong	Genetic Variation	[8]
Charcot-Marie-Tooth disease type 2	DISR30O9	Strong	Biomarker	[9]
Charcot-Marie-Tooth disease X-linked recessive 4	DISGT6JW	Strong	X-linked	[10]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[11]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[12]
Diabetic kidney disease	DISJMWEY	Strong	Altered Expression	[13]
Epilepsy	DISBB28L	Strong	Biomarker	[14]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[15]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[3]
Glioma	DIS5RPEH	Strong	Biomarker	[16]
Intellectual disability	DISMBNXP	Strong	Biomarker	[17]
Lung cancer	DISCM4YA	Strong	Biomarker	[18]
Lung carcinoma	DISTR26C	Strong	Biomarker	[18]
Lung neoplasm	DISVARNB	Strong	Biomarker	[19]
Melanoma	DIS1RRCY	Strong	Genetic Variation	[20]
Mitochondrial complex I deficiency	DIS13M7V	Strong	Biomarker	[21]
Mitochondrial disease	DISKAHA3	Strong	Genetic Variation	[22]
Mitochondrial encephalomyopathy	DISA6PTN	Strong	Genetic Variation	[23]
Myopathy	DISOWG27	Strong	Genetic Variation	[24]
Neuronopathy, distal hereditary motor, type 5	DISTSHF6	Strong	Genetic Variation	[25]
Peripheral sensory neuropathies	DISYWI6M	Strong	Genetic Variation	[8]
Polyneuropathy	DISB9G3W	Strong	Genetic Variation	[26]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[27]
Retinitis pigmentosa	DISCGPY8	Strong	Therapeutic	[28]
Retinitis pigmentosa 1	DISSLQPP	Strong	Therapeutic	[28]
Severe X-linked mitochondrial encephalomyopathy	DISYTTXU	Strong	X-linked	[10]
Spondyloepimetaphyseal dysplasia, Bieganski type	DISWXMVZ	Strong	X-linked	[29]
Stroke	DISX6UHX	Strong	Altered Expression	[30]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[31]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[32]
Juvenile Huntington disease	DIS1IQJG	moderate	Biomarker	[33]
Leigh syndrome	DISWQU45	Moderate	X-linked	[2]
Auditory neuropathy	DISM6GAU	Disputed	Genetic Variation	[34]
Parkinson disease	DISQVHKL	Disputed	Biomarker	[35]
Asthma	DISW9QNS	Limited	Biomarker	[36]
Huntington disease	DISQPLA4	Limited	Biomarker	[37]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
URSOLIC ACID	DM4SOAW	Phase 2	Apoptosis-inducing factor 1, mitochondrial (AIFM1) decreases the response to substance of URSOLIC ACID.	[92]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[39]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[52]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[78]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[52]

32 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 Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[40]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[41]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[42]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[43]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[44]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[45]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[46]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[47]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[49]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[50]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[51]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[54]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[56]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[50]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[58]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[59]
Acocantherin	DM7JT24	Approved	Acocantherin increases the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[62]
Phenylephrine	DMZHUO5	Approved	Phenylephrine increases the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[67]
Ropivacaine	DMSPJG2	Approved	Ropivacaine increases the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[68]
Clonidine	DM6RZ9Q	Approved	Clonidine increases the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[69]
Norfloxacin	DMIZ6W2	Approved	Norfloxacin increases the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[71]
Oxybuprocaine	DMI0GDH	Approved	Oxybuprocaine increases the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[72]
Rubitecan	DMDWU1S	Phase 3	Rubitecan increases the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[75]
Thymoquinone	DMVDTR2	Phase 2/3	Thymoquinone increases the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[76]
Tetrandrine	DMAOJBX	Phase 1	Tetrandrine increases the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[79]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[81]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[82]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[83]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[84]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[85]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos increases the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[86]
ELLAGIC ACID	DMX8BS5	Investigative	ELLAGIC ACID increases the expression of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[88]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide affects the localization of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[48]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the cleavage of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[53]
Bortezomib	DMNO38U	Approved	Bortezomib affects the localization of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[55]
Dasatinib	DMJV2EK	Approved	Dasatinib affects the localization of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[57]
Sulindac	DM2QHZU	Approved	Sulindac affects the localization of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[60]
Capsaicin	DMGMF6V	Approved	Capsaicin affects the localization of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[61]
Sorafenib	DMS8IFC	Approved	Sorafenib affects the localization of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[63]
Nitric Oxide	DM1RBYG	Approved	Nitric Oxide affects the localization of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[64]
Artesunate	DMR27C8	Approved	Artesunate affects the localization of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[65]
Sulfasalazine	DMICA9H	Approved	Sulfasalazine affects the localization of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[66]
Cilostazol	DMZMSCT	Approved	Cilostazol increases the localization of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[70]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the secretion of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[73]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate affects the localization of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[74]
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[77]
Adaphostin	DM16QSG	Phase 1	Adaphostin increases the secretion of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[80]
AEW-541	DMQF982	Phase 1	AEW-541 affects the localization of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[57]
acrolein	DMAMCSR	Investigative	acrolein affects the localization of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[87]
PD98059	DMZC90M	Investigative	PD98059 affects the localization of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[89]
3,7,3',4'-TETRAHYDROXYFLAVONE	DMES906	Investigative	3,7,3',4'-TETRAHYDROXYFLAVONE increases the localization of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[90]
MANGOSTIN	DMYQGDV	Investigative	MANGOSTIN affects the localization of Apoptosis-inducing factor 1, mitochondrial (AIFM1).	[91]

References

• [1] Proteomic analysis of childhood de novo acute myeloid leukemia and myelodysplastic syndrome/AML: correlation to molecular and cytogenetic analyses.Amino Acids. 2011 Mar;40(3):943-51. doi: 10.1007/s00726-010-0718-9. Epub 2010 Aug 14.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Allograft inflammatory factor-1 defines a distinct subset of infiltrating macrophages/microglial cells in rat and human gliomas.Acta Neuropathol. 2000 Dec;100(6):673-80. doi: 10.1007/s004010000233.
• [4] Young children who screen positive for autism: Stability, change and "comorbidity" over two years.Res Dev Disabil. 2018 Jan;72:297-307. doi: 10.1016/j.ridd.2016.10.004. Epub 2016 Nov 3.
• [5] Suppression of oncoprotein Her-2 and DNA damage after treatment with Flavan-3- ol vitis labrusca extract.Anticancer Agents Med Chem. 2013 Sep;13(7):1088-95. doi: 10.2174/18715206113139990135.
• [6] Clinical spectrum of AIFM1-associated disease in an Irish family, from mild neuropathy to severe cerebellar ataxia with colour blindness.J Peripher Nerv Syst. 2019 Dec;24(4):348-353. doi: 10.1111/jns.12348. Epub 2019 Oct 10.
• [7] Modeling Dynamic Contrast-Enhanced MRI Data with a Constrained Local AIF.Mol Imaging Biol. 2018 Feb;20(1):150-159. doi: 10.1007/s11307-017-1090-x.
• [8] A novel AIFM1 mutation in a Chinese family with X-linked Charcot-Marie-Tooth disease type 4.Neuromuscul Disord. 2018 Aug;28(8):652-659. doi: 10.1016/j.nmd.2018.05.008. Epub 2018 May 26.
• [9] A novel type of hereditary motor and sensory neuropathy characterized by a mild phenotype.Arch Neurol. 1999 Oct;56(10):1283-8. doi: 10.1001/archneur.56.10.1283.
• [10] Cowchock syndrome is associated with a mutation in apoptosis-inducing factor. Am J Hum Genet. 2012 Dec 7;91(6):1095-102. doi: 10.1016/j.ajhg.2012.10.008.
• [11] AIF suppresses chemical stress-induced apoptosis and maintains the transformed state of tumor cells.EMBO J. 2005 Aug 3;24(15):2815-26. doi: 10.1038/sj.emboj.7600746. Epub 2005 Jul 7.
• [12] SNHG15 is a bifunctional MYC-regulated noncoding locus encoding a lncRNA that promotes cell proliferation, invasion and drug resistance in colorectal cancer by interacting with AIF.J Exp Clin Cancer Res. 2019 Apr 24;38(1):172. doi: 10.1186/s13046-019-1169-0.
• [13] Deficiency in Apoptosis-Inducing Factor Recapitulates Chronic Kidney Disease via Aberrant Mitochondrial Homeostasis.Diabetes. 2016 Apr;65(4):1085-98. doi: 10.2337/db15-0864. Epub 2016 Jan 28.
• [14] TRPM2 ion channel is involved in the aggravation of cognitive impairment and down regulation of epilepsy threshold in pentylenetetrazole-induced kindling mice.Brain Res Bull. 2020 Feb;155:48-60. doi: 10.1016/j.brainresbull.2019.11.018. Epub 2019 Nov 30.
• [15] Implications of Bit1 and AIF overexpressions in esophageal squamous cell carcinoma.Tumour Biol. 2014 Jan;35(1):519-27. doi: 10.1007/s13277-013-1073-8. Epub 2013 Aug 17.
• [16] Deoxypodophyllotoxin triggers parthanatos in glioma cells via induction of excessive ROS.Cancer Lett. 2016 Feb 28;371(2):194-204. doi: 10.1016/j.canlet.2015.11.044. Epub 2015 Dec 9.
• [17] Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation - a novel phenotype of the mitochondrial disease. Clin Genet. 2017 Jan;91(1):30-37. doi: 10.1111/cge.12792. Epub 2016 Jun 2.
• [18] Artesunate induces apoptosis via a Bak-mediated caspase-independent intrinsic pathway in human lung adenocarcinoma cells.J Cell Physiol. 2012 Dec;227(12):3778-86. doi: 10.1002/jcp.24086.
• [19] The extract of Hibiscus syriacus inducing apoptosis by activating p53 and AIF in human lung cancer cells.Am J Chin Med. 2008;36(1):171-84. doi: 10.1142/S0192415X08005680.
• [20] Differential modulatory effects of GSK-3 and HDM2 on sorafenib-induced AIF nuclear translocation (programmed necrosis) in melanoma.Mol Cancer. 2011 Sep 19;10:115. doi: 10.1186/1476-4598-10-115.
• [21] The variability of the harlequin mouse phenotype resembles that of human mitochondrial-complex I-deficiency syndromes.PLoS One. 2008 Sep 15;3(9):e3208. doi: 10.1371/journal.pone.0003208.
• [22] Apoptosis-Inducing Factor (AIF) in Physiology and Disease: The Tale of a Repented Natural Born Killer.EBioMedicine. 2018 Apr;30:29-37. doi: 10.1016/j.ebiom.2018.03.016. Epub 2018 Mar 23.
• [23] Mutations in AIFM1 cause an X-linked childhood cerebellar ataxia partially responsive to riboflavin.Eur J Paediatr Neurol. 2018 Jan;22(1):93-101. doi: 10.1016/j.ejpn.2017.09.004. Epub 2017 Sep 15.
• [24] A disease-associated Aifm1 variant induces severe myopathy in knockin mice.Mol Metab. 2018 Jul;13:10-23. doi: 10.1016/j.molmet.2018.05.002. Epub 2018 May 8.
• [25] Compound heterozygous mutations in glycyl-tRNA synthetase (GARS) cause mitochondrial respiratory chain dysfunction.PLoS One. 2017 Jun 8;12(6):e0178125. doi: 10.1371/journal.pone.0178125. eCollection 2017.
• [26] A novel missense mutation in AIFM1 results in axonal polyneuropathy and misassembly of OXPHOS complexes.Eur J Neurol. 2017 Dec;24(12):1499-1506. doi: 10.1111/ene.13452. Epub 2017 Oct 7.
• [27] The enzymatic activity of apoptosis-inducing factor supports energy metabolism benefiting the growth and invasiveness of advanced prostate cancer cells.J Biol Chem. 2012 Dec 21;287(52):43862-75. doi: 10.1074/jbc.M112.407650. Epub 2012 Nov 1.
• [28] Inhibitory peptide of mitochondrial -calpain protects against photoreceptor degeneration in rhodopsin transgenic S334ter and P23H rats.PLoS One. 2013 Aug 9;8(8):e71650. doi: 10.1371/journal.pone.0071650. eCollection 2013.
• [29] X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1. Neurogenetics. 2017 Dec;18(4):185-194. doi: 10.1007/s10048-017-0520-x. Epub 2017 Aug 26.
• [30] Bcl-2 transfection via herpes simplex virus blocks apoptosis-inducing factor translocation after focal ischemia in the rat.J Cereb Blood Flow Metab. 2004 Jun;24(6):681-92. doi: 10.1097/01.WCB.0000127161.89708.A5.
• [31] Luteolin induces apoptotic cell death through AIF nuclear translocation mediated by activation of ERK and p38 in human breast cancer cell lines.Cell Biol Int. 2012 Apr 1;36(4):339-44. doi: 10.1042/CBI20110394.
• [32] Overexpression of apoptosis-inducing factor mitochondrion-associated 1 (AIFM1) induces apoptosis by promoting the transcription of caspase3 and DRAM in hepatoma cells.Biochem Biophys Res Commun. 2018 Apr 6;498(3):453-457. doi: 10.1016/j.bbrc.2018.02.203. Epub 2018 Mar 1.
• [33] Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington's disease.Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10483-7. doi: 10.1073/pnas.1832501100. Epub 2003 Aug 20.
• [34] AUNX1, a novel locus responsible for X linked recessive auditory and peripheral neuropathy, maps to Xq23-27.3.J Med Genet. 2006 Jul;43(7):e33. doi: 10.1136/jmg.2005.037929.
• [35] Expression changes of genes associated with apoptosis and survival processes in Parkinson's disease.Neurosci Lett. 2016 Feb 26;615:72-7. doi: 10.1016/j.neulet.2016.01.029. Epub 2016 Jan 22.
• [36] Activation of Bcl-2-Caspase-9 Apoptosis Pathway in the Testis of Asthmatic Mice.PLoS One. 2016 Mar 3;11(3):e0149353. doi: 10.1371/journal.pone.0149353. eCollection 2016.
• [37] Huntingtin protein interactions altered by polyglutamine expansion as determined by quantitative proteomic analysis.Cell Cycle. 2012 May 15;11(10):2006-21. doi: 10.4161/cc.20423. Epub 2012 May 15.
• [38] Protective effect of FGF21 on type 1 diabetes-induced testicular apoptotic cell death probably via both mitochondrial- and endoplasmic reticulum stress-dependent pathways in the mouse model.Toxicol Lett. 2013 May 10;219(1):65-76. doi: 10.1016/j.toxlet.2013.02.022. Epub 2013 Mar 7.
• [39] 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.
• [40] 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.
• [41] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [42] 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.
• [43] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [44] Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):117-27.
• [45] 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.
• [46] 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.
• [47] Quercetin induced cell apoptosis and altered gene expression in AGS human gastric cancer cells. Environ Toxicol. 2018 Nov;33(11):1168-1181. doi: 10.1002/tox.22623. Epub 2018 Aug 27.
• [48] Arsenic trioxide-induced death of neuroblastoma cells involves activation of Bax and does not require p53. Clin Cancer Res. 2004 May 1;10(9):3179-88. doi: 10.1158/1078-0432.ccr-03-0309.
• [49] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [50] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [51] 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.
• [52] 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.
• [53] Growth inhibition of ovarian tumor-initiating cells by niclosamide. Mol Cancer Ther. 2012 Aug;11(8):1703-12.
• [54] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [55] Differential regulation of noxa in normal melanocytes and melanoma cells by proteasome inhibition: therapeutic implications. Cancer Res. 2005 Jul 15;65(14):6294-304. doi: 10.1158/0008-5472.CAN-05-0686.
• [56] Marked regression of liver metastasis by combined therapy of ultrasound-mediated NF kappaB-decoy transfer and transportal injection of paclitaxel, in mouse. Int J Cancer. 2008 Apr 1;122(7):1645-56. doi: 10.1002/ijc.23280.
• [57] Co-administration of NVP-AEW541 and dasatinib induces mitochondrial-mediated apoptosis through Bax activation in malignant human glioma cell lines. Int J Oncol. 2010 Sep;37(3):633-43. doi: 10.3892/ijo_00000712.
• [58] 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.
• [59] Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling. PLoS One. 2007 Nov 14;2(11):e1187. doi: 10.1371/journal.pone.0001187.
• [60] Sulindac activates nuclear translocation of AIF, DFF40 and endonuclease G but not induces oligonucleosomal DNA fragmentation in HT-29 cells. Life Sci. 2005 Sep 2;77(16):2059-70. doi: 10.1016/j.lfs.2005.04.021.
• [61] Capsaicin induces apoptosis in SCC-4 human tongue cancer cells through mitochondria-dependent and -independent pathways. Environ Toxicol. 2012 May;27(6):332-41. doi: 10.1002/tox.20646. Epub 2010 Oct 5.
• [62] Ouabain induces apoptotic cell death in human prostate DU 145 cancer cells through DNA damage and TRAIL pathways. Environ Toxicol. 2019 Dec;34(12):1329-1339. doi: 10.1002/tox.22834. Epub 2019 Aug 21.
• [63] Apoptosis induced by the kinase inhibitor BAY 43-9006 in human leukemia cells involves down-regulation of Mcl-1 through inhibition of translation. J Biol Chem. 2005 Oct 21;280(42):35217-27. doi: 10.1074/jbc.M506551200. Epub 2005 Aug 18.
• [64] Apoptotic signaling pathways induced by nitric oxide in human lymphoblastoid cells expressing wild-type or mutant p53. Cancer Res. 2004 May 1;64(9):3022-9. doi: 10.1158/0008-5472.can-03-1880.
• [65] Artesunate induces apoptosis through caspase-dependent and -independent mitochondrial pathways in human myelodysplastic syndrome SKM-1 cells. Chem Biol Interact. 2014 Aug 5;219:28-36. doi: 10.1016/j.cbi.2014.03.011. Epub 2014 Apr 3.
• [66] Molecular mechanisms of sulfasalazine-induced T-cell apoptosis. Br J Pharmacol. 2002 Nov;137(5):608-20. doi: 10.1038/sj.bjp.0704870.
• [67] Phenylephrine induces necroptosis and apoptosis in corneal epithelial cells dose- and time-dependently. Toxicology. 2019 Dec 1;428:152305. doi: 10.1016/j.tox.2019.152305. Epub 2019 Oct 9.
• [68] Effect of parthanatos on ropivacaine-induced damage in SH-SY5Y cells. Clin Exp Pharmacol Physiol. 2017 May;44(5):586-594. doi: 10.1111/1440-1681.12730.
• [69] Clonidine Induces Apoptosis of Human Corneal Epithelial Cells through Death Receptors-Mediated, Mitochondria-Dependent Signaling Pathway. Toxicol Sci. 2017 Mar 1;156(1):252-260. doi: 10.1093/toxsci/kfw249.
• [70] Cilostazol enhances apoptosis of synovial cells from rheumatoid arthritis patients with inhibition of cytokine formation via Nrf2-linked heme oxygenase 1 induction. Arthritis Rheum. 2010 Mar;62(3):732-41. doi: 10.1002/art.27291.
• [71] Norfloxacin induces apoptosis and necroptosis in human corneal epithelial cells. Toxicol In Vitro. 2020 Aug;66:104868. doi: 10.1016/j.tiv.2020.104868. Epub 2020 Apr 19.
• [72] The cytotoxic effect of oxybuprocaine on human corneal epithelial cells by inducing cell cycle arrest and mitochondria-dependent apoptosis. Hum Exp Toxicol. 2017 Aug;36(8):765-775. doi: 10.1177/0960327116665676. Epub 2016 Sep 1.
• [73] Resveratrol induces apoptosis via a Bak-mediated intrinsic pathway in human lung adenocarcinoma cells. Cell Signal. 2012 May;24(5):1037-46. doi: 10.1016/j.cellsig.2011.12.025. Epub 2012 Jan 5.
• [74] Green tea component, catechin, induces apoptosis of human malignant B cells via production of reactive oxygen species. Clin Cancer Res. 2005 Aug 15;11(16):6040-9. doi: 10.1158/1078-0432.CCR-04-2273.
• [75] Characterization of 9-nitrocamptothecin liposomes: anticancer properties and mechanisms on hepatocellular carcinoma in vitro and in vivo. PLoS One. 2011;6(6):e21064. doi: 10.1371/journal.pone.0021064. Epub 2011 Jun 9.
• [76] Thymoquinone induces apoptosis in bladder cancer cell via endoplasmic reticulum stress-dependent mitochondrial pathway. Chem Biol Interact. 2018 Aug 25;292:65-75. doi: 10.1016/j.cbi.2018.06.013. Epub 2018 Jul 2.
• [77] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [78] 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.
• [79] Tetrandrine induces programmed cell death in human oral cancer CAL 27 cells through the reactive oxygen species production and caspase-dependent pathways and associated with beclin-1-induced cell autophagy. Environ Toxicol. 2017 Jan;32(1):329-343. doi: 10.1002/tox.22238. Epub 2016 Jan 29.
• [80] Induction of apoptosis in human leukemia cells by the tyrosine kinase inhibitor adaphostin proceeds through a RAF-1/MEK/ERK- and AKT-dependent process. Oncogene. 2004 Feb 19;23(7):1364-76. doi: 10.1038/sj.onc.1207248.
• [81] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [82] A synthetic coumarin derivative (4-flourophenylacetamide-acetyl coumarin) impedes cell cycle at G0/G1 stage, induces apoptosis, and inhibits metastasis via ROS-mediated p53 and AKT signaling pathways in A549 cells. J Biochem Mol Toxicol. 2020 Oct;34(10):e22553. doi: 10.1002/jbt.22553. Epub 2020 Jun 24.
• [83] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [84] Central role of Nix in the autophagic response to ochratoxin A. Food Chem Toxicol. 2014 Jul;69:202-9. doi: 10.1016/j.fct.2014.04.017. Epub 2014 Apr 19.
• [85] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [86] Organophosphate-pesticides induced survival mechanisms and APE1-mediated Nrf2 regulation in non-small-cell lung cancer cells. J Biochem Mol Toxicol. 2021 Feb;35(2):e22640. doi: 10.1002/jbt.22640. Epub 2020 Oct 20.
• [87] Acrolein induces a cellular stress response and triggers mitochondrial apoptosis in A549 cells. Chem Biol Interact. 2009 Oct 7;181(2):154-67. doi: 10.1016/j.cbi.2009.07.001. Epub 2009 Jul 9.
• [88] Ellagic acid induces apoptosis in TSGH8301 human bladder cancer cells through the endoplasmic reticulum stress- and mitochondria-dependent signaling pathways. Environ Toxicol. 2014 Nov;29(11):1262-74. doi: 10.1002/tox.21857. Epub 2013 Mar 30.
• [89] Inhibition of extracellular signal regulated kinase (ERK) leads to apoptosis inducing factor (AIF) mediated apoptosis in epithelial breast cancer cells: the lack of effect of ERK in p53 mediated copper induced apoptosis. J Cell Biochem. 2005 Aug 15;95(6):1120-34. doi: 10.1002/jcb.20484.
• [90] Fisetin-induced apoptosis of human oral cancer SCC-4 cells through reactive oxygen species production, endoplasmic reticulum stress, caspase-, and mitochondria-dependent signaling pathways. Environ Toxicol. 2017 Jun;32(6):1725-1741. doi: 10.1002/tox.22396. Epub 2017 Feb 9.
• [91] -Mangostin-induced apoptosis is mediated by estrogen receptor in human breast cancer cells. Food Chem Toxicol. 2014 Apr;66:158-65. doi: 10.1016/j.fct.2014.01.040. Epub 2014 Jan 28.
• [92] Ursolic acid induces doxorubicin-resistant HepG2 cell death via the release of apoptosis-inducing factor. Cancer Lett. 2010 Dec 1;298(1):128-38. doi: 10.1016/j.canlet.2010.06.010. Epub 2010 Jul 13.