Details of the Drug Combination

General Information of Drug Combination (ID: DC6JP7D)

• Drug Combination Name: Levamisole + Methoxsalen
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Levamisole (DM5EN79): Small molecular drug
  Methoxsalen (DME8FZ9): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 69.43
  Bliss Independence Score: 69.43
  Loewe Additivity Score: 83.15
  LHighest Single Agent (HSA) Score: 83.15

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Levamisole

Disease Entry	ICD 11	Status	REF
Parasitic infection	1D0Y-1G2Z	Approved	[2]
Colon cancer	2B90.Z	Withdrawn from market	[3]

Levamisole Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Alkaline phosphatase tissue-nonspecific (ALPL)	TTMR5UV	PPBT_HUMAN	Inhibitor	[6]

Levamisole Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Expression	[7]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Increases Expression	[7]

Indication(s) of Methoxsalen

Disease Entry	ICD 11	Status	REF
Cutaneous T-cell lymphoma	2B01	Approved	[4]
Primary cutaneous T-cell lymphoma	N.A.	Approved	[5]
Psoriasis vulgaris	EA90	Approved	[4]

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	[9]

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	[10]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[11]

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	[10]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[10]
Class E basic helix-loop-helix protein 40 (BHLHE40)	OTITX14U	BHE40_HUMAN	Decreases Expression	[12]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[12]
ATP-binding cassette sub-family C member 3 (ABCC3)	OTC3IJV4	MRP3_HUMAN	Increases Expression	[8]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[13]
Phosphatidylcholine translocator ABCB4 (ABCB4)	OTE6PY83	MDR3_HUMAN	Decreases Expression	[14]
Nuclear receptor subfamily 0 group B member 2 (NR0B2)	OT7UVICX	NR0B2_HUMAN	Increases Expression	[8]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Increases Expression	[13]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] 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: 7210).
• [4] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 009048.
• [5] Methoxsalen FDA Label
• [6] Characterization of rat heart alkaline phosphatase isoenzymes and modulation of activity. Braz J Med Biol Res. 2008 Jul;41(7):600-9.
• [7] Levamisole induced apoptosis in cultured vascular endothelial cells. Br J Pharmacol. 2000 Dec;131(8):1577-83.
• [8] 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.
• [9] Mutagenicity and carcinogenicity of methoxsalen plus UV-A. Arch Dermatol. 1984 May;120(5):662-9.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.