Details of the Drug Combination

General Information of Drug Combination (ID: DCK3TK6)

• Drug Combination Name: EMODIN + Idarubicin
• Indication: Glioblastoma?; Status: Investigative [1]
• Component Drugs:
  EMODIN (DMAEDQG): Small molecular drug
  Idarubicin (DMM0XGL): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: T98G
  Zero Interaction Potency (ZIP) Score: 16.22
  Bliss Independence Score: 16.22
  Loewe Additivity Score: 1.8
  LHighest Single Agent (HSA) Score: 1.8

Molecular Interaction Atlas of This Drug Combination

Indication(s) of EMODIN

Disease Entry	ICD 11	Status	REF
Coronavirus Disease 2019 (COVID-19)	1D6Y	Investigative	[2]

EMODIN Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Casein kinase II alpha (CSNK2A1)	TTER6YH	CSK21_HUMAN	Inhibitor	[11]

EMODIN Interacts with 89 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Increases Expression	[12]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Increases Expression	[12]
Etoposide-induced protein 2.4 homolog (EI24)	OTD4NOYS	EI24_HUMAN	Increases Expression	[5]
Protein phosphatase 1D (PPM1D)	OT8NLZ9D	PPM1D_HUMAN	Increases Expression	[5]
Growth arrest-specific protein 2 (GAS2)	OT50JKXQ	GAS2_HUMAN	Increases Expression	[5]
Rho-associated protein kinase 2 (ROCK2)	OTVYN14T	ROCK2_HUMAN	Decreases Expression	[5]
G2/mitotic-specific cyclin-B2 (CCNB2)	OTIEXTDK	CCNB2_HUMAN	Decreases Expression	[5]
Dihydrofolate reductase (DHFR)	OT3DVIGM	DYR_HUMAN	Decreases Expression	[5]
RAF proto-oncogene serine/threonine-protein kinase (RAF1)	OT51LSFO	RAF1_HUMAN	Decreases Expression	[5]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Expression	[5]
Glutathione peroxidase 1 (GPX1)	OTE2O72Q	GPX1_HUMAN	Increases Expression	[5]
Cathepsin D (CTSD)	OTQZ36F3	CATD_HUMAN	Decreases Expression	[5]
Keratin, type I cytoskeletal 19 (KRT19)	OTDGDQ75	K1C19_HUMAN	Decreases Expression	[5]
Microtubule-associated protein tau (MAPT)	OTMTP2Z7	TAU_HUMAN	Decreases Expression	[5]
Cyclin-dependent kinase 4 (CDK4)	OT7EP05T	CDK4_HUMAN	Decreases Expression	[5]
Glutathione S-transferase Mu 3 (GSTM3)	OTLA2WJT	GSTM3_HUMAN	Decreases Expression	[5]
DnaJ homolog subfamily B member 1 (DNAJB1)	OTCOSEVH	DNJB1_HUMAN	Increases Expression	[5]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Increases Expression	[5]
Calnexin (CANX)	OTYP1F6J	CALX_HUMAN	Decreases Expression	[5]
Peroxiredoxin-6 (PRDX6)	OTS8KC8A	PRDX6_HUMAN	Increases Expression	[5]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Expression	[5]
Stress-induced-phosphoprotein 1 (STIP1)	OT7TXLOX	STIP1_HUMAN	Decreases Expression	[5]
Transforming protein RhoA (RHOA)	OT6YOJ9N	RHOA_HUMAN	Decreases Expression	[5]
Actin, alpha skeletal muscle (ACTA1)	OTOVGLPG	ACTS_HUMAN	Decreases Expression	[5]
Protein kinase C delta type (PRKCD)	OTSEH90E	KPCD_HUMAN	Decreases Expression	[5]
Forkhead box protein O1 (FOXO1)	OTPJRB6D	FOXO1_HUMAN	Increases Expression	[5]
TNF receptor-associated factor 2 (TRAF2)	OT1MEZZN	TRAF2_HUMAN	Increases Expression	[5]
Serine-protein kinase ATM (ATM)	OTQVOHLT	ATM_HUMAN	Increases Expression	[5]
Phosducin-like protein (PDCL)	OTDNHIXG	PHLP_HUMAN	Decreases Expression	[5]
Rho-associated protein kinase 1 (ROCK1)	OTSXYVW1	ROCK1_HUMAN	Decreases Expression	[5]
Cyclin-dependent kinase 13 (CDK13)	OT3P7JF1	CDK13_HUMAN	Decreases Expression	[5]
Translation initiation factor eIF2B subunit alpha (EIF2B1)	OT4NCVY1	EI2BA_HUMAN	Decreases Expression	[5]
Reticulocalbin-2 (RCN2)	OTIU8JWD	RCN2_HUMAN	Increases Expression	[5]
Inositol 1,4,5-trisphosphate receptor type 1 (ITPR1)	OTX7MWW1	ITPR1_HUMAN	Decreases Expression	[5]
Transcription factor E2F5 (E2F5)	OT1XWING	E2F5_HUMAN	Increases Expression	[5]
Tubulin-specific chaperone C (TBCC)	OTBF0X8R	TBCC_HUMAN	Decreases Expression	[5]
Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3)	OTLUM9L7	PK3C3_HUMAN	Increases Expression	[5]
Transcription factor SPT20 homolog (SUPT20H)	OTTMC0LH	SP20H_HUMAN	Increases Expression	[5]
Alpha-N-acetylneuraminide alpha-2,8-sialyltransferase (ST8SIA1)	OTGND2YZ	SIA8A_HUMAN	Increases Expression	[5]
Serine/threonine-protein kinase TAO3 (TAOK3)	OTYBATSH	TAOK3_HUMAN	Decreases Expression	[5]
Cadherin EGF LAG seven-pass G-type receptor 3 (CELSR3)	OT8P6QNJ	CELR3_HUMAN	Decreases Expression	[5]
Bifunctional apoptosis regulator (BFAR)	OTTBG0V7	BFAR_HUMAN	Decreases Expression	[5]
Very-long-chain (HACD3)	OTISMCAF	HACD3_HUMAN	Decreases Expression	[5]
SUMO-activating enzyme subunit 1 (SAE1)	OT18HFX5	SAE1_HUMAN	Decreases Expression	[5]
BAG family molecular chaperone regulator 5 (BAG5)	OT0J97C6	BAG5_HUMAN	Decreases Expression	[5]
Microtubule-actin cross-linking factor 1, isoforms 1/2/3/4/5 (MACF1)	OTVIHD77	MACF1_HUMAN	Decreases Expression	[5]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Decreases Activity	[13]
Sulfotransferase 1A1 (SULT1A1)	OT0K7JIE	ST1A1_HUMAN	Decreases Activity	[13]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[7]
Aldo-keto reductase family 1 member B10 (AKR1B10)	OTOA4HTH	AK1BA_HUMAN	Decreases Activity	[14]
Tyrosine-protein kinase JAK2 (JAK2)	OTBIDOOR	JAK2_HUMAN	Decreases Phosphorylation	[7]
Microphthalmia-associated transcription factor (MITF)	OT6XJCZH	MITF_HUMAN	Decreases Expression	[6]
Aflatoxin B1 aldehyde reductase member 3 (AKR7A3)	OTW3GO4Y	ARK73_HUMAN	Decreases Activity	[14]
Estrogen receptor (ESR1)	OTKLU61J	ESR1_HUMAN	Increases Activity	[15]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[16]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Activity	[7]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[7]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Decreases Activity	[17]
DNA topoisomerase 2-alpha (TOP2A)	OT6LPS08	TOP2A_HUMAN	Increases Activity	[18]
Proto-oncogene tyrosine-protein kinase Src (SRC)	OTETYX40	SRC_HUMAN	Decreases Phosphorylation	[7]
NAD(P)H dehydrogenase 1 (NQO1)	OTZGGIVK	NQO1_HUMAN	Increases Expression	[16]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Expression	[19]
Carbonyl reductase 1 (CBR1)	OTQ3A541	CBR1_HUMAN	Decreases Activity	[14]
Platelet endothelial cell adhesion molecule (PECAM1)	OTXOM4D9	PECA1_HUMAN	Decreases Expression	[7]
Tyrosine-protein kinase JAK1 (JAK1)	OT0X3D17	JAK1_HUMAN	Decreases Phosphorylation	[7]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[20]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[20]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[20]
Tyrosine-protein phosphatase non-receptor type 6 (PTPN6)	OT33XNZM	PTN6_HUMAN	Increases Expression	[7]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Increases Expression	[21]
L-dopachrome tautomerase (DCT)	OTYVNTBG	TYRP2_HUMAN	Decreases Expression	[6]
Signal transducer and activator of transcription 3 (STAT3)	OTAAGKYZ	STAT3_HUMAN	Affects Localization	[7]
Hepatocyte nuclear factor 4-alpha (HNF4A)	OTY1TOAB	HNF4A_HUMAN	Decreases Expression	[8]
Aldo-keto reductase family 1 member C3 (AKR1C3)	OTU2SXBA	AK1C3_HUMAN	Decreases Activity	[14]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[7]
Tumor necrosis factor ligand superfamily member 6 (FASLG)	OTZARCHH	TNFL6_HUMAN	Increases Expression	[20]
BH3-interacting domain death agonist (BID)	OTOSHSHU	BID_HUMAN	Increases Degradation	[20]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Affects Expression	[20]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[7]
Oxysterols receptor LXR-alpha (NR1H3)	OT54YZ9I	NR1H3_HUMAN	Increases Expression	[6]
Maternal embryonic leucine zipper kinase (MELK)	OTEY2UQA	MELK_HUMAN	Decreases Expression	[22]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[20]
Solute carrier family 22 member 6 (SLC22A6)	OTKRCBVM	S22A6_HUMAN	Decreases Activity	[23]
Organic anion transporter 3 (SLC22A8)	OT8BY933	S22A8_HUMAN	Decreases Activity	[23]
Estrogen receptor beta (ESR2)	OTXNR2WQ	ESR2_HUMAN	Increases Activity	[15]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Increases Oxidation	[24]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases Hydroxylation	[25]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Hydroxylation	[25]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Increases Hydroxylation	[25]

Indication(s) of Idarubicin

Disease Entry	ICD 11	Status	REF
Acute myelogenous leukaemia	2A41	Approved	[3]
Acute myeloid leukaemia	2A60	Approved	[4]
Adult acute monocytic leukemia	N.A.	Approved	[3]
Childhood acute megakaryoblastic leukemia	N.A.	Approved	[3]
Leukemia	N.A.	Approved	[3]

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	[27]

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	[28]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[29]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[29]

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	[30]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[30]

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	[26]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[31]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Increases Activity	[26]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Increases Expression	[32]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Decreases Activity	[26]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[33]
Peroxisome proliferator-activated receptor delta (PPARD)	OTI4WTOP	PPARD_HUMAN	Decreases Activity	[26]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[34]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Decreases Activity	[26]

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] Naturally Occurring Anthraquinones as Potential Inhibitors of SARS-CoV-2 Main Protease: A Molecular Docking Study. May 7, 2020
• [3] Idarubicin FDA Label
• [4] 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).
• [5] Gene expression alteration during redox-dependent enhancement of arsenic cytotoxicity by emodin in HeLa cells. Cell Res. 2005 Jul;15(7):511-22.
• [6] Emodin isolated from Polygoni Multiflori Ramulus inhibits melanogenesis through the liver X receptor-mediated pathway. Chem Biol Interact. 2016 Apr 25;250:78-84. doi: 10.1016/j.cbi.2016.03.014. Epub 2016 Mar 10.
• [7] Emodin inhibits growth and induces apoptosis in an orthotopic hepatocellular carcinoma model by blocking activation of STAT3. Br J Pharmacol. 2013 Oct;170(4):807-21. doi: 10.1111/bph.12302.
• [8] Metabolism and Toxicity of Emodin: Genome-Wide Association Studies Reveal Hepatocyte Nuclear Factor 4 Regulates UGT2B7 and Emodin Glucuronidation. Chem Res Toxicol. 2020 Jul 20;33(7):1798-1808. doi: 10.1021/acs.chemrestox.0c00047. Epub 2020 Jul 7.
• [9] Stable expression of a human liver UDP-glucuronosyltransferase (UGT2B15) with activity toward steroid and xenobiotic substrates. Drug Metab Dispos. 1994 Sep-Oct;22(5):799-805.
• [10] Differential and special properties of the major human UGT1-encoded gastrointestinal UDP-glucuronosyltransferases enhance potential to control chemical uptake. J Biol Chem. 2004 Jan 9;279(2):1429-41.
• [11] Structural insight into human CK2alpha in complex with the potent inhibitor ellagic acid. Bioorg Med Chem Lett. 2009 Jun 1;19(11):2920-3.
• [12] Induction of cytochromes P450 1A1 and 1B1 by emodin in human lung adenocarcinoma cell line CL5. Drug Metab Dispos. 2001 Sep;29(9):1229-35.
• [13] The natural anthraquinones from Rheum palmatum induced the metabolic disorder of melatonin by inhibiting human CYP and SULT enzymes. Toxicol Lett. 2016 Nov 16;262:27-38.
• [14] Inhibition of human carbonyl reducing enzymes by plant anthrone and anthraquinone derivatives. Chem Biol Interact. 2022 Feb 25;354:109823. doi: 10.1016/j.cbi.2022.109823. Epub 2022 Jan 21.
• [15] Validation of a new yeast-based reporter assay consisting of human estrogen receptors alpha/beta and coactivator SRC-1: application for detection of estrogenic activity in environmental samples. Environ Toxicol. 2009 Oct;24(5):513-21. doi: 10.1002/tox.20473.
• [16] Inhibition of CYP3A4 enhances aloe-emodin induced hepatocyte injury. Toxicol In Vitro. 2022 Mar;79:105276. doi: 10.1016/j.tiv.2021.105276. Epub 2021 Dec 4.
• [17] Anthraquinones inhibit cytochromes P450 enzyme activity in silico and in vitro. J Appl Toxicol. 2021 Sep;41(9):1438-1445. doi: 10.1002/jat.4134. Epub 2021 Jan 12.
• [18] Emodin triggers DNA double-strand breaks by stabilizing topoisomerase II-DNA cleavage complexes and by inhibiting ATP hydrolysis of topoisomerase II. Toxicol Sci. 2010 Dec;118(2):435-43. doi: 10.1093/toxsci/kfq282. Epub 2010 Sep 20.
• [19] Insight into the practical models for prediciting the essential role of the cytochrome P450-mediated biotransformation in emodin-associated hepatotoxicity. Toxicology. 2021 Oct;462:152930. doi: 10.1016/j.tox.2021.152930. Epub 2021 Sep 4.
• [20] Involvement of PI3K/Akt, ERK and p38 signaling pathways in emodin-mediated extrinsic and intrinsic human hepatoblastoma cell apoptosis. Food Chem Toxicol. 2016 Jun;92:26-37. doi: 10.1016/j.fct.2016.03.013. Epub 2016 Mar 23.
• [21] Involvement of PPAR in emodin-induced HK-2 cell apoptosis. Toxicol In Vitro. 2015 Feb;29(1):228-33. doi: 10.1016/j.tiv.2014.10.021.
• [22] Structure-based virtual screening of chemical libraries as potential MELK inhibitors and their therapeutic evaluation against breast cancer. Chem Biol Interact. 2023 May 1;376:110443. doi: 10.1016/j.cbi.2023.110443. Epub 2023 Mar 8.
• [23] From the Cover: Identification of Natural Products as Inhibitors of Human Organic Anion Transporters (OAT1 and OAT3) and Their Protective Effect on Mercury-Induced Toxicity. Toxicol Sci. 2018 Feb 1;161(2):321-334. doi: 10.1093/toxsci/kfx216.
• [24] Chemical Reactivity of Emodin and Its Oxidative Metabolites to Thiols. Chem Res Toxicol. 2016 Dec 19;29(12):2114-2124. doi: 10.1021/acs.chemrestox.6b00191. Epub 2016 Nov 30.
• [25] Chemical Reactivity of Aloe-Emodin and Its Hydroxylation Metabolites to Thiols. Chem Res Toxicol. 2019 Feb 18;32(2):234-244. doi: 10.1021/acs.chemrestox.8b00248. Epub 2019 Feb 6.
• [26] 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.
• [27] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [28] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [29] Amonafide L-malate is not a substrate for multidrug resistance proteins in secondary acute myeloid leukemia. Leukemia. 2008 Nov;22(11):2110-5.
• [30] In vitro evaluation of cytochrome P450-mediated drug interactions between cytarabine, idarubicin, itraconazole and caspofungin. Hematology. 2004 Jun;9(3):217-21.
• [31] 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.
• [32] The use of biochemical markers in cardiotoxicity monitoring in patients treated for leukemia. Neoplasma. 2005;52(5):430-4.
• [33] 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.
• [34] 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.