Details of the Drug Combination

General Information of Drug Combination (ID: DCNOOTI)

• Drug Combination Name: Methoxsalen + Hydralazine
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Methoxsalen (DME8FZ9): Small molecular drug
  Hydralazine (DMU8JGH): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 0.15
  Bliss Independence Score: 0.15
  Loewe Additivity Score: 11.92
  LHighest Single Agent (HSA) Score: 11.92

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Methoxsalen

Disease Entry	ICD 11	Status	REF
Cutaneous T-cell lymphoma	2B01	Approved	[2]
Primary cutaneous T-cell lymphoma	N.A.	Approved	[3]
Psoriasis vulgaris	EA90	Approved	[2]

Methoxsalen Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2A6 (CYP2A6)	TTAQ6ZW	CP2A6_HUMAN	Binder	[7]

Methoxsalen Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[8]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[9]

Methoxsalen Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cocaine esterase (CES2)	OTC647SQ	EST2_HUMAN	Increases Expression	[8]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[8]
Class E basic helix-loop-helix protein 40 (BHLHE40)	OTITX14U	BHE40_HUMAN	Decreases Expression	[10]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[10]
ATP-binding cassette sub-family C member 3 (ABCC3)	OTC3IJV4	MRP3_HUMAN	Increases Expression	[6]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[11]
Phosphatidylcholine translocator ABCB4 (ABCB4)	OTE6PY83	MDR3_HUMAN	Decreases Expression	[12]
Nuclear receptor subfamily 0 group B member 2 (NR0B2)	OT7UVICX	NR0B2_HUMAN	Increases Expression	[6]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Increases Expression	[11]

Indication(s) of Hydralazine

Disease Entry	ICD 11	Status	REF
Chronic heart failure	BD1Z	Approved	[4]
Hypertension	BA00-BA04	Approved	[5]
Malignant essential hypertension	BA00	Approved	[4]

Hydralazine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Membrane copper amine oxidase (AOC3)	TT7HC21	AOC3_HUMAN	Modulator	[13]

Hydralazine Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
RNA cytidine acetyltransferase (hALP)	DEZV4AP	NAT10_HUMAN	Metabolism	[14]
N-acetyltransferase 1 (NAT1)	DE7OAB3	ARY1_HUMAN	Metabolism	[15]
N-acetyltransferase 2 (NAT2)	DER7TA0	ARY2_HUMAN	Metabolism	[15]

Hydralazine Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Arylamine N-acetyltransferase 2 (NAT2)	OTBPDQOY	ARY2_HUMAN	Increases Acetylation	[16]
Methylated-DNA--protein-cysteine methyltransferase (MGMT)	OT40A9WH	MGMT_HUMAN	Increases Expression	[17]
Adenomatous polyposis coli protein (APC)	OTKV0TIK	APC_HUMAN	Decreases Methylation	[17]
Cyclin-dependent kinase inhibitor 2A (CDKN2A)	OTN0ZWAE	CDN2A_HUMAN	Decreases Methylation	[17]
Bis(5'-adenosyl)-triphosphatase (FHIT)	OTGWBSLA	FHIT_HUMAN	Increases Expression	[17]
Death-associated protein kinase 1 (DAPK1)	OTNCNUCO	DAPK1_HUMAN	Increases Expression	[17]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Activity	[18]
Collagen alpha-1(I) chain (COL1A1)	OTI31178	CO1A1_HUMAN	Decreases Expression	[19]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[20]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 009048.
• [3] Methoxsalen FDA Label
• [4] Hydralazine FDA Label
• [5] 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: 7326).
• [6] Adaptive homeostasis of the vitamin D-vitamin D nuclear receptor axis in 8-methoxypsoralen-induced hepatotoxicity. Toxicol Appl Pharmacol. 2019 Jan 1;362:150-158. doi: 10.1016/j.taap.2018.11.002. Epub 2018 Nov 10.
• [7] Mutagenicity and carcinogenicity of methoxsalen plus UV-A. Arch Dermatol. 1984 May;120(5):662-9.
• [8] Photochemotherapeutic agent 8-methoxypsoralen induces cytochrome P450 3A4 and carboxylesterase HCE2: evidence on an involvement of the pregnane X receptor. Toxicol Sci. 2007 Jan;95(1):13-22.
• [9] Identification of the human cytochrome P450 enzymes involved in the in vitro metabolism of artemisinin. Br J Clin Pharmacol. 1999 Oct;48(4):528-35.
• [10] Down regulation of differentiated embryonic chondrocytes 1 (DEC1) is involved in 8-methoxypsoralen-induced apoptosis in HepG2 cells. Toxicology. 2012 Nov 15;301(1-3):58-65. doi: 10.1016/j.tox.2012.06.022. Epub 2012 Jul 11.
• [11] ABC-transporter blockage mediated by xanthotoxin and bergapten is the major pathway for chemosensitization of multidrug-resistant cancer cells. Toxicol Appl Pharmacol. 2017 Dec 15;337:22-29. doi: 10.1016/j.taap.2017.10.018. Epub 2017 Oct 25.
• [12] 8-Methoxypsoralen disrupts MDR3-mediated phospholipids efflux and bile acid homeostasis and its relevance to hepatotoxicity. Toxicology. 2017 Jul 1;386:40-48. doi: 10.1016/j.tox.2017.05.011. Epub 2017 May 24.
• [13] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [14] Prizidilol, an antihypertensive with precapillary vasodilator and beta-adrenoceptor blocking actions, in primary hypertension. Clin Pharmacol Ther. 1981 May;29(5):588-93.
• [15] N-acetyltransferase 2 genotype-dependent N-acetylation of hydralazine in human hepatocytes. Drug Metab Dispos. 2017 Dec;45(12):1276-1281.
• [16] Eukaryotic arylamine N-acetyltransferase. Investigation of substrate specificity by high-throughput screening. Biochem Pharmacol. 2005 Jan 15;69(2):347-59. doi: 10.1016/j.bcp.2004.09.014. Epub 2004 Nov 24.
• [17] A phase I study of hydralazine to demethylate and reactivate the expression of tumor suppressor genes. BMC Cancer. 2005 Apr 29;5:44.
• [18] Sympathetic activity in idiopathic dilated cardiomyopathy. Influence of captopril and hydralazine. Cardiovasc Drugs Ther. 1987 Aug;1(2):177-81. doi: 10.1007/BF02125471.
• [19] Hydralazine inhibits human peritoneal mesothelial cell proliferation and collagen synthesis. Nephrol Dial Transplant. 1996 Nov;11(11):2276-81. doi: 10.1093/oxfordjournals.ndt.a027148.
• [20] Albumin Protects Lung Cells against Acrolein Cytotoxicity and Acrolein-Adducted Albumin Increases Heme Oxygenase 1 Transcripts. Chem Res Toxicol. 2020 Jul 20;33(7):1969-1979. doi: 10.1021/acs.chemrestox.0c00146. Epub 2020 Jun 29.