Details of the Drug Combination

General Information of Drug Combination (ID: DCI0UAM)

• Drug Combination Name: Tacrine + Furazolidone
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Tacrine (DM51FY6): Small molecular drug
  Furazolidone (DM3P6V7): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 4.6
  Bliss Independence Score: 4.6
  Loewe Additivity Score: 19.38
  LHighest Single Agent (HSA) Score: 19.38

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Tacrine

Disease Entry	ICD 11	Status	REF
Alzheimer disease	8A20	Approved	[2]

Tacrine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Acetylcholinesterase (AChE)	TT1RS9F	ACES_HUMAN	Inhibitor	[4]

Tacrine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[5]

Tacrine Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[6]
Glutathione S-transferase alpha-1 (GSTA1)	DE4ZHS1	GSTA1_HUMAN	Metabolism	[7]

Tacrine Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cocaine esterase (CES2)	OTC647SQ	EST2_HUMAN	Decreases Activity	[8]
Phosphatidylcholine translocator ABCB4 (ABCB4)	OTE6PY83	MDR3_HUMAN	Decreases Activity	[9]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[10]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[10]

Indication(s) of Furazolidone

Disease Entry	ICD 11	Status	REF
Diarrhea	ME05.1	Approved	[3]

Furazolidone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial Deoxyribonucleic acid (Bact DNA)	TTS1W4A	NOUNIPROTAC	Modulator	[11]

Furazolidone Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Serine/threonine-protein kinase Chk1 (CHEK1)	OTTTI622	CHK1_HUMAN	Increases Expression	[12]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[13]
Growth arrest and DNA damage-inducible protein GADD45 alpha (GADD45A)	OTDRV63V	GA45A_HUMAN	Increases Expression	[14]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[12]
G1/S-specific cyclin-D3 (CCND3)	OTNKPQ22	CCND3_HUMAN	Increases Expression	[15]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[12]
Breast cancer type 1 susceptibility protein (BRCA1)	OT5BN6VH	BRCA1_HUMAN	Increases Expression	[12]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[13]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] 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: 6687).
• [3] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 011270.
• [4] Evidence that the clinical effects of cholinesterase inhibitors are related to potency and targeting of action. Int J Clin Pract Suppl. 2002 Jun;(127):6-19.
• [5] Tacrine sinusoidal uptake and biliary excretion in sandwich-cultured primary rat hepatocytes. J Pharm Pharm Sci. 2014;17(3):427-38.
• [6] Synthetic and natural compounds that interact with human cytochrome P450 1A2 and implications in drug development. Curr Med Chem. 2009;16(31):4066-218.
• [7] Combined glutathione-S-transferase M1 and T1 genetic polymorphism and tacrine hepatotoxicity. Clin Pharmacol Ther. 2000 Apr;67(4):432-7.
• [8] Inhibition of human carboxylesterases hCE1 and hiCE by cholinesterase inhibitors. Chem Biol Interact. 2013 Mar 25;203(1):226-30.
• [9] Evaluating the Role of Multidrug Resistance Protein 3 (MDR3) Inhibition in Predicting Drug-Induced Liver Injury Using 125 Pharmaceuticals. Chem Res Toxicol. 2017 May 15;30(5):1219-1229. doi: 10.1021/acs.chemrestox.7b00048. Epub 2017 May 4.
• [10] High-content imaging-based BAC-GFP toxicity pathway reporters to assess chemical adversity liabilities. Arch Toxicol. 2017 Mar;91(3):1367-1383. doi: 10.1007/s00204-016-1781-0. Epub 2016 Jun 29.
• [11] Interaction of furazolidone with DNA. Biochim Biophys Acta. 1975 Aug 21;402(2):161-5.
• [12] Involvement of the activation of Nrf2/HO-1, p38 MAPK signaling pathways and endoplasmic reticulum stress in furazolidone induced cytotoxicity and S phase arrest in human hepatocyte L02 cells: modulation of curcumin. Toxicol Mech Methods. 2017 Mar;27(3):165-172. doi: 10.1080/15376516.2016.1273424. Epub 2017 Jan 8.
• [13] P21(Waf1/Cip1) plays a critical role in furazolidone-induced apoptosis in HepG2 cells through influencing the caspase-3 activation and ROS generation. Food Chem Toxicol. 2016 Feb;88:1-12. doi: 10.1016/j.fct.2015.12.004. Epub 2015 Dec 11.
• [14] The Effect of GADD45a on Furazolidone-Induced S-Phase Cell-Cycle Arrest in Human Hepatoma G2 Cells. J Biochem Mol Toxicol. 2015 Oct;29(10):489-495. doi: 10.1002/jbt.21719. Epub 2015 Jun 11.
• [15] Involvement of the p38 MAPK signaling pathway in S-phase cell-cycle arrest induced by Furazolidone in human hepatoma G2 cells. J Appl Toxicol. 2013 Dec;33(12):1500-5. doi: 10.1002/jat.2829. Epub 2012 Oct 30.