Details of the Drug Combination

General Information of Drug Combination (ID: DC2X0PS)

• Drug Combination Name: 3,7,3',4'-TETRAHYDROXYFLAVONE + Idarubicin
• Indication: Glioblastoma?; Status: Investigative [1]
• Component Drugs:
  3,7,3',4'-TETRAHYDROXYFLAVONE (DMES906): Small molecular drug
  Idarubicin (DMM0XGL): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: T98G
  Zero Interaction Potency (ZIP) Score: 22.11
  Bliss Independence Score: 22.11
  Loewe Additivity Score: 3.93
  LHighest Single Agent (HSA) Score: 3.93

Molecular Interaction Atlas of This Drug Combination

Indication(s) of 3,7,3',4'-TETRAHYDROXYFLAVONE

Disease Entry	ICD 11	Status	REF
Discovery agent	N.A.	Investigative	[2]

3,7,3',4'-TETRAHYDROXYFLAVONE Interacts with 5 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Plasmodium Beta-hydroxyacyl-ACP dehydratase (Malaria FabZ)	TTHPFTS	Q965D7_PLAFA	Inhibitor	[7]
Fatty acid synthase (FASN)	TT7AOUD	FAS_HUMAN	Inhibitor	[7]
Plasmodium Enoyl-ACP reductase (Malaria fabI)	TTNX2CS	Q965D5_PLAFA	Inhibitor	[7]
Plasmodium Oxoacyl-[acyl-carrier protein] reductase (Malaria fabG)	TTBE4IR	Q965D6_PLAFA	Inhibitor	[7]
Cyclin-dependent kinase 6 (CDK6)	TTO0FDJ	CDK6_HUMAN	Inhibitor	[2]

3,7,3',4'-TETRAHYDROXYFLAVONE Interacts with 29 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Expression	[8]
Serine/threonine-protein kinase Chk1 (CHEK1)	OTTTI622	CHK1_HUMAN	Increases Expression	[9]
Apoptosis-inducing factor 1, mitochondrial (AIFM1)	OTKPWB7Q	AIFM1_HUMAN	Increases Localization	[9]
Serine/threonine-protein kinase Chk2 (CHEK2)	OT8ZPCNS	CHK2_HUMAN	Increases Expression	[9]
Calpain-1 catalytic subunit (CAPN1)	OTK6OQZR	CAN1_HUMAN	Increases Expression	[9]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Decreases Activity	[10]
Cadherin-1 (CDH1)	OTFJMXPM	CADH1_HUMAN	Increases Expression	[5]
CD44 antigen (CD44)	OT9TTJ41	CD44_HUMAN	Decreases Expression	[5]
Calpain-2 catalytic subunit (CAPN2)	OTIAPE5J	CAN2_HUMAN	Increases Expression	[9]
Cyclic AMP-dependent transcription factor ATF-6 alpha (ATF6)	OTAFHAVI	ATF6A_HUMAN	Increases Expression	[9]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Decreases Expression	[5]
Receptor tyrosine-protein kinase erbB-3 (ERBB3)	OTRSST0A	ERBB3_HUMAN	Decreases Expression	[11]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[12]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[12]
CCN family member 2 (CCN2)	OTC39NSU	CCN2_HUMAN	Decreases Expression	[13]
M-phase inducer phosphatase 3 (CDC25C)	OTPQI71S	MPIP3_HUMAN	Decreases Expression	[9]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Decreases Expression	[5]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[9]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[14]
Tumor necrosis factor ligand superfamily member 6 (FASLG)	OTZARCHH	TNFL6_HUMAN	Increases Expression	[14]
BH3-interacting domain death agonist (BID)	OTOSHSHU	BID_HUMAN	Increases Cleavage	[14]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[13]
Sterol regulatory element-binding protein 2 (SREBF2)	OTBXUNPL	SRBP2_HUMAN	Increases Expression	[15]
Endonuclease G, mitochondrial (ENDOG)	OT5IM7B3	NUCG_HUMAN	Increases Localization	[9]
Inactive caspase-12 (CASP12)	OTY2W6FG	CASPC_HUMAN	Increases Expression	[9]
Type II iodothyronine deiodinase (DIO2)	OTGPNSLH	IOD2_HUMAN	Increases Activity	[16]
Cyclic AMP-dependent transcription factor ATF-6 beta (ATF6B)	OTT2ZGSR	ATF6B_HUMAN	Increases Expression	[9]
Serine/threonine-protein kinase LATS2 (LATS2)	OT6XO8JP	LATS2_HUMAN	Increases Phosphorylation	[13]
Mitogen-activated protein kinase kinase kinase 20 (MAP3K20)	OT0ALMEG	M3K20_HUMAN	Increases Expression	[13]

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	[18]

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	[19]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[20]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[20]

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	[21]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[21]

Idarubicin Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Increases Expression	[22]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Decreases Activity	[17]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [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] Fisetin suppresses migration, invasion and stem-cell-like phenotype of human non-small cell lung carcinoma cells via attenuation of epithelial to mesenchymal transition. Chem Biol Interact. 2019 Apr 25;303:14-21. doi: 10.1016/j.cbi.2019.02.020. Epub 2019 Feb 22.
• [6] 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.
• [7] Inhibition of Plasmodium falciparum fatty acid biosynthesis: evaluation of FabG, FabZ, and FabI as drug targets for flavonoids. J Med Chem. 2006 Jun 1;49(11):3345-53.
• [8] Stable cellular models of nuclear receptor PXR for high-throughput evaluation of small molecules. Toxicol In Vitro. 2018 Oct;52:222-234.
• [9] 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.
• [10] Dietary flavones and flavonoles are inhibitors of poly(ADP-ribose)polymerase-1 in pulmonary epithelial cells. J Nutr. 2007 Oct;137(10):2190-5. doi: 10.1093/jn/137.10.2190.
• [11] Fisetin induces apoptosis in breast cancer MDA-MB-453 cells through degradation of HER2/neu and via the PI3K/Akt pathway. J Biochem Mol Toxicol. 2019 Apr;33(4):e22268. doi: 10.1002/jbt.22268. Epub 2018 Nov 15.
• [12] Fisetin induces apoptosis in human cervical cancer HeLa cells through ERK1/2-mediated activation of caspase-8-/caspase-3-dependent pathway. Arch Toxicol. 2012 Feb;86(2):263-73. doi: 10.1007/s00204-011-0754-6. Epub 2011 Oct 1.
• [13] Fisetin activates Hippo pathway and JNK/ERK/AP-1 signaling to inhibit proliferation and induce apoptosis of human osteosarcoma cells via ZAK overexpression. Environ Toxicol. 2019 Aug;34(8):902-911. doi: 10.1002/tox.22761. Epub 2019 May 1.
• [14] Anticancer activity of a combination of cisplatin and fisetin in embryonal carcinoma cells and xenograft tumors. Mol Cancer Ther. 2011 Feb;10(2):255-68. doi: 10.1158/1535-7163.MCT-10-0606. Epub 2011 Jan 7.
• [15] Hypocholesterolemic effect of daily fisetin supplementation in high fat fed Sprague-Dawley rats. Food Chem Toxicol. 2013 Jul;57:84-90. doi: 10.1016/j.fct.2013.03.010. Epub 2013 Mar 21.
• [16] The small polyphenolic molecule kaempferol increases cellular energy expenditure and thyroid hormone activation. Diabetes. 2007 Mar;56(3):767-76. doi: 10.2337/db06-1488.
• [17] 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.
• [18] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [19] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [20] Amonafide L-malate is not a substrate for multidrug resistance proteins in secondary acute myeloid leukemia. Leukemia. 2008 Nov;22(11):2110-5.
• [21] In vitro evaluation of cytochrome P450-mediated drug interactions between cytarabine, idarubicin, itraconazole and caspofungin. Hematology. 2004 Jun;9(3):217-21.
• [22] The use of biochemical markers in cardiotoxicity monitoring in patients treated for leukemia. Neoplasma. 2005;52(5):430-4.