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 26 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2A6 (CYP2A6)	OT52TWG3	CP2A6_HUMAN	Decreases Activity	[10]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[8]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Decreases Activity	[11]
Cocaine esterase (CES2)	OTC647SQ	EST2_HUMAN	Increases Expression	[8]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[8]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Decreases Activity	[12]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Decreases Activity	[12]
Class E basic helix-loop-helix protein 40 (BHLHE40)	OTITX14U	BHE40_HUMAN	Decreases Expression	[13]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[13]
ATP-binding cassette sub-family C member 3 (ABCC3)	OTC3IJV4	MRP3_HUMAN	Increases Expression	[6]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Expression	[14]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[13]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[15]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[16]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[13]
Phosphatidylcholine translocator ABCB4 (ABCB4)	OTE6PY83	MDR3_HUMAN	Decreases Expression	[17]
Cytochrome P450 7A1 (CYP7A1)	OT8Z5KLD	CP7A1_HUMAN	Decreases Expression	[6]
Multidrug resistance-associated protein 1 (ABCC1)	OTGUN89S	MRP1_HUMAN	Increases Expression	[16]
Histidine ammonia-lyase (HAL)	OT1HXFCV	HUTH_HUMAN	Decreases Activity	[18]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Decreases Expression	[13]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[13]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Decreases Expression	[13]
Nuclear receptor subfamily 0 group B member 2 (NR0B2)	OT7UVICX	NR0B2_HUMAN	Increases Expression	[6]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[15]
ATP-binding cassette sub-family C member 2 (ABCC2)	OTJSIGV5	MRP2_HUMAN	Decreases Expression	[16]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Increases Expression	[16]

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	[19]

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	[20]
N-acetyltransferase 1 (NAT1)	DE7OAB3	ARY1_HUMAN	Metabolism	[21]
N-acetyltransferase 2 (NAT2)	DER7TA0	ARY2_HUMAN	Metabolism	[21]

Hydralazine Interacts with 16 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Arylamine N-acetyltransferase 2 (NAT2)	OTBPDQOY	ARY2_HUMAN	Increases Acetylation	[22]
Estrogen receptor (ESR1)	OTKLU61J	ESR1_HUMAN	Increases Expression	[23]
Glutathione S-transferase P (GSTP1)	OTLP0A0Y	GSTP1_HUMAN	Increases Expression	[23]
Retinoic acid receptor beta (RARB)	OT367U3E	RARB_HUMAN	Decreases Methylation	[23]
Methylated-DNA--protein-cysteine methyltransferase (MGMT)	OT40A9WH	MGMT_HUMAN	Increases Expression	[23]
Adenomatous polyposis coli protein (APC)	OTKV0TIK	APC_HUMAN	Decreases Methylation	[23]
Cyclin-dependent kinase inhibitor 2A (CDKN2A)	OTN0ZWAE	CDN2A_HUMAN	Decreases Methylation	[23]
Bis(5'-adenosyl)-triphosphatase (FHIT)	OTGWBSLA	FHIT_HUMAN	Increases Expression	[23]
Death-associated protein kinase 1 (DAPK1)	OTNCNUCO	DAPK1_HUMAN	Increases Expression	[23]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Activity	[24]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Secretion	[25]
Collagen alpha-1(I) chain (COL1A1)	OTI31178	CO1A1_HUMAN	Decreases Expression	[26]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[27]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Activity	[28]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Secretion	[25]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Increases Secretion	[25]

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] 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] Mimicking gene defects to treat drug dependence. Ann N Y Acad Sci. 2000;909:233-46. doi: 10.1111/j.1749-6632.2000.tb06685.x.
• [11] Specificity of substrate and inhibitor probes for cytochrome P450s: evaluation of in vitro metabolism using cDNA-expressed human P450s and human liver microsomes. Xenobiotica. 1996 Jul;26(7):681-93.
• [12] Functional expression and comparative characterization of nine murine cytochromes P450 by fluorescent inhibition screening. Drug Metab Dispos. 2008 Jul;36(7):1322-31.
• [13] 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.
• [14] UVA activated 8-MOP and chlorpromazine inhibit release of TNF-alpha by post-transcriptional regulation. Photochem Photobiol Sci. 2004 Apr;3(4):334-6. doi: 10.1039/b302621c. Epub 2004 Feb 24.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Inhibition of histidine ammonia lyase by 8-methoxypsoralen and psoralen-oxidized photoproducts. Photochem Photobiol. 2010 Nov-Dec;86(6):1272-7. doi: 10.1111/j.1751-1097.2010.00807.x. Epub 2010 Sep 29.
• [19] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [20] Prizidilol, an antihypertensive with precapillary vasodilator and beta-adrenoceptor blocking actions, in primary hypertension. Clin Pharmacol Ther. 1981 May;29(5):588-93.
• [21] N-acetyltransferase 2 genotype-dependent N-acetylation of hydralazine in human hepatocytes. Drug Metab Dispos. 2017 Dec;45(12):1276-1281.
• [22] 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.
• [23] A phase I study of hydralazine to demethylate and reactivate the expression of tumor suppressor genes. BMC Cancer. 2005 Apr 29;5:44.
• [24] Sympathetic activity in idiopathic dilated cardiomyopathy. Influence of captopril and hydralazine. Cardiovasc Drugs Ther. 1987 Aug;1(2):177-81. doi: 10.1007/BF02125471.
• [25] Antihypertensive drugs clonidine, diazoxide, hydralazine and furosemide regulate the production of cytokines by placentas and peripheral blood mononuclear cells in normal pregnancy. J Hypertens. 2006 May;24(5):915-22. doi: 10.1097/01.hjh.0000222762.84605.03.
• [26] 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.
• [27] 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.
• [28] High-throughput measurement of the Tp53 response to anticancer drugs and random compounds using a stably integrated Tp53-responsive luciferase reporter. Carcinogenesis. 2002 Jun;23(6):949-57. doi: 10.1093/carcin/23.6.949.