Details of the Drug Combination

General Information of Drug Combination (ID: DCVGATN)

Drug Combination Name

Disulfiram Idarubicin

Indication

Disease Entry	Status	REF
Glioblastoma?	Investigative	[1]

Component Drugs

Disulfiram DMCL2OK

Idarubicin DMM0XGL

Small molecular drug

2D MOL

3D MOL

High-throughput Screening Result

Testing Cell Line: T98G

Zero Interaction Potency (ZIP) Score: 10.25

Bliss Independence Score: 10.25

Loewe Additivity Score: 4.5

LHighest Single Agent (HSA) Score: 4.5

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)

Indication(s) of Disulfiram

Disease Entry	ICD 11	Status	REF
Alcohol dependence	6C40.2	Approved	[2]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Investigative	[3]
Middle East Respiratory Syndrome (MERS)	1D64	Investigative	[4]
Severe acute respiratory syndrome (SARS)	1D65	Investigative	[4]

Disulfiram Interacts with 4 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
MERS-CoV papain-like proteinase (PL-PRO)	TTYJOLE	R1AB_CVEMC (854-2740)	Inhibitor	[4]
Fatty aldehyde dehydrogenase (ALDH3A2)	TTB6UM0	AL3A2_HUMAN	Inhibitor	[8]
COVID-19 papain-like proteinase (PL-PRO)	TTNHMO8	R1AB_SARS2 (819-2763)	Inhibitor	[3]
SARS-CoV papain-like proteinase (PL-PRO)	TTRGHB2	R1AB_CVHSA (819-2740)	Inhibitor	[4]
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Disulfiram Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[9]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[10]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[11]
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Disulfiram Interacts with 73 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Retinaldehyde dehydrogenase 3 (ALDH1A3)	OT1C9NKQ	AL1A3_HUMAN	Increases ADR	[12]
Dopamine beta-hydroxylase (DBH)	OTC6I2SP	DOPO_HUMAN	Decreases Activity	[13]
Cytochrome P450 2E1 (CYP2E1)	OTHQ17JG	CP2E1_HUMAN	Decreases Activity	[14]
Multidrug resistance-associated protein 1 (ABCC1)	OTGUN89S	MRP1_HUMAN	Decreases Activity	[15]
Metallothionein-2 (MT2A)	OTHOACHD	MT2_HUMAN	Increases Expression	[16]
Metallothionein-1F (MT1F)	OTZVUYG1	MT1F_HUMAN	Increases Expression	[16]
Metallothionein-1B (MT1B)	OTUA4FFH	MT1B_HUMAN	Increases Expression	[16]
Metallothionein-1G (MT1G)	OTAV1OCR	MT1G_HUMAN	Increases Expression	[16]
DNA replication licensing factor MCM5 (MCM5)	OTAHLB62	MCM5_HUMAN	Decreases Expression	[16]
DNA replication licensing factor MCM2 (MCM2)	OTGGORIQ	MCM2_HUMAN	Decreases Expression	[16]
Metallothionein-1X (MT1X)	OT9AKFVS	MT1X_HUMAN	Increases Expression	[16]
Transcription factor MafG (MAFG)	OTBQFUZH	MAFG_HUMAN	Increases Expression	[7]
Aldo-keto reductase family 1 member B10 (AKR1B10)	OTOA4HTH	AK1BA_HUMAN	Increases Expression	[7]
Transcription factor MafK (MAFK)	OTZJUE4P	MAFK_HUMAN	Increases Expression	[7]
Glutathione reductase, mitochondrial (GSR)	OTM2TUYM	GSHR_HUMAN	Increases Expression	[7]
Superoxide dismutase (SOD1)	OT39TA1L	SODC_HUMAN	Increases Expression	[7]
Ferritin light chain (FTL)	OTYQA8A6	FRIL_HUMAN	Increases Expression	[7]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[7]
Extracellular superoxide dismutase (SOD3)	OTIOZQAB	SODE_HUMAN	Increases Expression	[7]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[7]
Heat shock 70 kDa protein 1A (HSPA1A)	OTKGIE76	HS71A_HUMAN	Increases Expression	[7]
Microsomal glutathione S-transferase 1 (MGST1)	OTGN1KVZ	MGST1_HUMAN	Increases Expression	[7]
Glucose-6-phosphate 1-dehydrogenase (G6PD)	OT300SMK	G6PD_HUMAN	Increases Expression	[7]
Aldo-keto reductase family 1 member B1 (AKR1B1)	OTRX72TH	ALDR_HUMAN	Increases Expression	[7]
NAD(P)H dehydrogenase 1 (NQO1)	OTZGGIVK	NQO1_HUMAN	Increases Expression	[7]
Glutathione peroxidase 3 (GPX3)	OT6PK94R	GPX3_HUMAN	Increases Expression	[7]
Ferrochelatase, mitochondrial (FECH)	OTDWEI6C	HEMH_HUMAN	Increases Expression	[7]
Aldo-keto reductase family 1 member C3 (AKR1C3)	OTU2SXBA	AK1C3_HUMAN	Increases Expression	[7]
NADP-dependent malic enzyme (ME1)	OTSVEUQE	MAOX_HUMAN	Increases Expression	[7]
Glutamate--cysteine ligase catalytic subunit (GCLC)	OTESDI4D	GSH1_HUMAN	Increases Expression	[7]
Glutamate--cysteine ligase regulatory subunit (GCLM)	OT6CP234	GSH0_HUMAN	Increases Expression	[7]
6-phosphogluconate dehydrogenase, decarboxylating (PGD)	OTVG296F	6PGD_HUMAN	Increases Expression	[7]
Aldo-keto reductase family 1 member C1 (AKR1C1)	OTQKR4CM	AK1C1_HUMAN	Increases Expression	[7]
Prostaglandin reductase 1 (PTGR1)	OTMAR351	PTGR1_HUMAN	Increases Expression	[7]
SPRY domain-containing SOCS box protein 1 (SPSB1)	OTGY26U4	SPSB1_HUMAN	Increases Expression	[7]
Sulfiredoxin-1 (SRXN1)	OTYDBO4L	SRXN1_HUMAN	Increases Expression	[7]
Transcription factor MafF (MAFF)	OT9B7MX0	MAFF_HUMAN	Increases Expression	[7]
Retinal dehydrogenase 2 (ALDH1A2)	OTJB560Z	AL1A2_HUMAN	Decreases Activity	[17]
Aldehyde dehydrogenase, mitochondrial (ALDH2)	OTKJ9I3N	ALDH2_HUMAN	Decreases Activity	[17]
11-beta-hydroxysteroid dehydrogenase type 2 (HSD11B2)	OTHF4H9U	DHI2_HUMAN	Decreases Activity	[18]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[19]
Aldehyde dehydrogenase 1A1 (ALDH1A1)	OTCUWZKB	AL1A1_HUMAN	Decreases Expression	[20]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Activity	[21]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases Secretion	[22]
Catalase (CAT)	OTHEBX9R	CATA_HUMAN	Decreases Expression	[22]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[23]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Activity	[24]
72 kDa type IV collagenase (MMP2)	OT5NIWA2	MMP2_HUMAN	Decreases Expression	[25]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[26]
Integrin alpha-M (ITGAM)	OTAG6HWU	ITAM_HUMAN	Increases Expression	[22]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Decreases Secretion	[22]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Decreases Expression	[25]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[27]
Methylated-DNA--protein-cysteine methyltransferase (MGMT)	OT40A9WH	MGMT_HUMAN	Increases Degradation	[28]
Platelet glycoprotein 4 (CD36)	OT5CZWKY	CD36_HUMAN	Decreases Expression	[22]
Cyclic AMP-dependent transcription factor ATF-3 (ATF3)	OTC1UOHP	ATF3_HUMAN	Increases Expression	[29]
Cystathionine gamma-lyase (CTH)	OTC90LA0	CGL_HUMAN	Increases Expression	[20]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Affects Expression	[22]
C-C chemokine receptor type 2 (CCR2)	OTQ7T10J	CCR2_HUMAN	Increases Expression	[22]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[30]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Increases Expression	[26]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[30]
Gasdermin-D (GSDMD)	OTH39BKI	GSDMD_HUMAN	Decreases Cleavage	[31]
Hemoglobin subunit gamma-2 (HBG2)	OT4J48JJ	HBG2_HUMAN	Increases Expression	[32]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[26]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[23]
Scavenger receptor cysteine-rich type 1 protein M130 (CD163)	OT2E32LN	C163A_HUMAN	Decreases Expression	[22]
Metallothionein-1M (MT1M)	OTVT8PLU	MT1M_HUMAN	Increases Expression	[29]
C-type lectin domain family 7 member A (CLEC7A)	OTRTBH27	CLC7A_HUMAN	Increases Expression	[22]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Decreases Expression	[33]
Aldehyde dehydrogenase, dimeric NADP-preferring (ALDH3A1)	OTAYZZE6	AL3A1_HUMAN	Increases Metabolism	[34]
Ataxin-3 (ATXN3)	OTJVVGKT	ATX3_HUMAN	Increases Response To Substance	[35]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Response To Substance	[36]
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⏷ Show the Full List of 73 DOT(s)

Indication(s) of Idarubicin

Disease Entry	ICD 11	Status	REF
Acute myelogenous leukaemia	2A41	Approved	[5]
Acute myeloid leukaemia	2A60	Approved	[6]
Adult acute monocytic leukemia	N.A.	Approved	[5]
Childhood acute megakaryoblastic leukemia	N.A.	Approved	[5]
Leukemia	N.A.	Approved	[5]

Idarubicin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
DNA topoisomerase II (TOP2)	TT0IHXV	TOP2A_HUMAN; TOP2B_HUMAN	Modulator	[38]
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Idarubicin Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 1 (ABCC1)	DTSYQGK	MRP1_HUMAN	Substrate	[39]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[40]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[40]
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Idarubicin Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[41]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[41]
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Idarubicin Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Estrogen receptor (ESR1)	OTKLU61J	ESR1_HUMAN	Decreases Activity	[37]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[42]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Increases Activity	[37]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Increases Expression	[43]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Decreases Activity	[37]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[44]
Peroxisome proliferator-activated receptor delta (PPARD)	OTI4WTOP	PPARD_HUMAN	Decreases Activity	[37]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[45]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Decreases Activity	[37]
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⏷ Show the Full List of 9 DOT(s)

References

1	Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
2	Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
3	Structure of Mpro from COVID-19 virus and discovery of its inhibitors. Nature. 2020 Apr 9.
4	Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat Rev Drug Discov. 2020 Mar;19(3):149-150.
5	Idarubicin FDA Label
6	URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7083).
7	Keratinocyte gene expression profiles discriminate sensitizing and irritating compounds. Toxicol Sci. 2010 Sep;117(1):81-9.
8	Pharmacological treatment of alcohol dependence: target symptoms and target mechanisms. Pharmacol Ther. 2006 Sep;111(3):855-76.
9	Interaction of disulfiram with antiretroviral medications: efavirenz increases while atazanavir decreases disulfiram effect on enzymes of alcohol metabolism. Am J Addict. 2014 Mar-Apr;23(2):137-44.
10	Identification of the human P-450 enzymes responsible for the sulfoxidation and thiono-oxidation of diethyldithiocarbamate methyl ester: role of P-450 enzymes in disulfiram bioactivation. Alcohol Clin Exp Res. 1998 Sep;22(6):1212-9.
11	Duration of cytochrome P-450 2E1 (CYP2E1) inhibition and estimation of functional CYP2E1 enzyme half-life after single-dose disulfiram administration in humans. J Pharmacol Exp Ther. 1999 Oct;291(1):213-9.
12	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.
13	Hypotension with anesthesia in disulfiram-treated patients. Anesthesiology. 1979 Oct;51(4):366-8.
14	Role of human cytochrome P-450 IIE1 in the oxidation of many low molecular weight cancer suspects. Chem Res Toxicol. 1991 Mar-Apr;4(2):168-79.
15	The molecular basis of the action of disulfiram as a modulator of the multidrug resistance-linked ATP binding cassette transporters MDR1 (ABCB1) and MRP1 (ABCC1). Mol Pharmacol. 2004 Mar;65(3):675-84.
16	High-throughput cell-based screening of 4910 known drugs and drug-like small molecules identifies disulfiram as an inhibitor of prostate cancer cell growth. Clin Cancer Res. 2009 Oct 1;15(19):6070-8.
17	The enzymatic activity of human aldehyde dehydrogenases 1A2 and 2 (ALDH1A2 and ALDH2) is detected by Aldefluor, inhibited by diethylaminobenzaldehyde and has significant effects on cell proliferation and drug resistance. Chem Biol Interact. 2012 Jan 5;195(1):52-60.
18	Species-specific differences in the inhibition of human and zebrafish 11beta-hydroxysteroid dehydrogenase 2 by thiram and organotins. Toxicology. 2012 Nov 15;301(1-3):72-8.
19	Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43.
20	The interaction of disulfiram and H(2)S metabolism in inhibition of aldehyde dehydrogenase activity and liver cancer cell growth. Toxicol Appl Pharmacol. 2021 Sep 1;426:115642. doi: 10.1016/j.taap.2021.115642. Epub 2021 Jul 6.
21	Identification and Profiling of Environmental Chemicals That Inhibit the TGF/SMAD Signaling Pathway. Chem Res Toxicol. 2019 Dec 16;32(12):2433-2444. doi: 10.1021/acs.chemrestox.9b00228. Epub 2019 Nov 11.
22	Comparative study of the effects of ziram and disulfiram on human monocyte-derived macrophage functions and polarization: involvement of zinc. Cell Biol Toxicol. 2021 Jun;37(3):379-400. doi: 10.1007/s10565-020-09540-6. Epub 2020 Jul 25.
23	Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.
24	Disulfiram metabolites permanently inactivate the human multidrug resistance P-glycoprotein. Mol Pharm. 2004 Nov-Dec;1(6):426-33. doi: 10.1021/mp049917l.
25	Disulfiram suppresses invasive ability of osteosarcoma cells via the inhibition of MMP-2 and MMP-9 expression. J Biochem Mol Biol. 2007 Nov 30;40(6):1069-76. doi: 10.5483/bmbrep.2007.40.6.1069.
26	Disulfiram, a clinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity. Cancer Res. 2006 Nov 1;66(21):10425-33. doi: 10.1158/0008-5472.CAN-06-2126.
27	Low-Dose Pesticides Alter Primary Human Bone Marrow Mesenchymal Stem/Stromal Cells through ALDH2 Inhibition. Cancers (Basel). 2021 Nov 14;13(22):5699. doi: 10.3390/cancers13225699.
28	Disulfiram is a direct and potent inhibitor of human O6-methylguanine-DNA methyltransferase (MGMT) in brain tumor cells and mouse brain and markedly increases the alkylating DNA damage. Carcinogenesis. 2014 Mar;35(3):692-702. doi: 10.1093/carcin/bgt366. Epub 2013 Nov 5.
29	Identification of novel activators of the metal responsive transcription factor (MTF-1) using a gene expression biomarker in a microarray compendium. Metallomics. 2020 Sep 23;12(9):1400-1415. doi: 10.1039/d0mt00071j.
30	Pharmacological profiling of disulfiram using human tumor cell lines and human tumor cells from patients. Biochem Pharmacol. 2007 Jan 1;73(1):25-33. doi: 10.1016/j.bcp.2006.08.016. Epub 2006 Aug 26.
31	Disulfiram inhibits inflammation and fibrosis in a rat unilateral ureteral obstruction model by inhibiting gasdermin D cleavage and pyroptosis. Inflamm Res. 2021 May;70(5):543-552. doi: 10.1007/s00011-021-01457-y. Epub 2021 Apr 13.
32	Cytochrome P(450)-dependent toxic effects of primaquine on human erythrocytes. Toxicol Appl Pharmacol. 2009 Nov 15;241(1):14-22. doi: 10.1016/j.taap.2009.07.012. Epub 2009 Jul 17.
33	Effect of common medications on the expression of SARS-CoV-2 entry receptors in liver tissue. Arch Toxicol. 2020 Dec;94(12):4037-4041. doi: 10.1007/s00204-020-02869-1. Epub 2020 Aug 17.
34	Contribution of aldehyde dehydrogenase 3A1 to disulfiram penetration through monolayers consisting of cultured human corneal epithelial cells. Biol Pharm Bull. 2008 Jul;31(7):1444-8. doi: 10.1248/bpb.31.1444.
35	Disulfiram facilitates ataxin-3 nuclear translocation and potentiates the cytotoxicity in a cell model of SCA3. J Toxicol Sci. 2019;44(8):535-542. doi: 10.2131/jts.44.535.
36	Development of a highly sensitive cytotoxicity assay system for CYP3A4-mediated metabolic activation. Drug Metab Dispos. 2011 Aug;39(8):1388-95. doi: 10.1124/dmd.110.037077. Epub 2011 May 3.
37	Quantitative high-throughput profiling of environmental chemicals and drugs that modulate farnesoid X receptor. Sci Rep. 2014 Sep 26;4:6437. doi: 10.1038/srep06437.
38	Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
39	Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
40	Amonafide L-malate is not a substrate for multidrug resistance proteins in secondary acute myeloid leukemia. Leukemia. 2008 Nov;22(11):2110-5.
41	In vitro evaluation of cytochrome P450-mediated drug interactions between cytarabine, idarubicin, itraconazole and caspofungin. Hematology. 2004 Jun;9(3):217-21.
42	A Quantitative Approach to Screen for Nephrotoxic Compounds In Vitro. J Am Soc Nephrol. 2016 Apr;27(4):1015-28. doi: 10.1681/ASN.2015010060. Epub 2015 Aug 10.
43	The use of biochemical markers in cardiotoxicity monitoring in patients treated for leukemia. Neoplasma. 2005;52(5):430-4.
44	The induction of apoptosis by daunorubicin and idarubicin in human trisomic and diabetic fibroblasts. Cell Mol Biol Lett. 2008;13(2):182-94. doi: 10.2478/s11658-007-0045-7. Epub 2008 Apr 10.
45	Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model. Toxicol Sci. 2013 Dec;136(2):581-94. doi: 10.1093/toxsci/kft205. Epub 2013 Sep 19.