Details of the Drug Combination

General Information of Drug Combination (ID: DC5559W)

• Drug Combination Name: Triamterene + Acitretin
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Triamterene (DM2HU9I): Small molecular drug
  Acitretin (DM8BKU9): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 9.6
  Bliss Independence Score: 9.6
  Loewe Additivity Score: 19.14
  LHighest Single Agent (HSA) Score: 19.14

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Triamterene

Disease Entry	ICD 11	Status	REF
Congestive heart failure	BD10	Approved	[2]
Edema	MG29	Approved	[2]
Hypertension	BA00-BA04	Approved	[2]
High blood pressure	BA00	Investigative	[3]

Triamterene Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Amiloride-sensitive sodium channel (ENaC)	TTQM7TE	SCNNA_HUMAN; SCNNB_HUMAN; SCNNG_HUMAN; SCNND_HUMAN	Blocker	[5]

Triamterene Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[6]

Triamterene Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[7]

Triamterene Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases Hydroxylation	[7]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Increases Activity	[8]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Affects Activity	[9]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Affects Response To Substance	[10]

Indication(s) of Acitretin

Disease Entry	ICD 11	Status	REF
Psoriasis vulgaris	EA90	Approved	[4]

Acitretin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Signal transducer and activator of transcription 3 (STAT3)	TTH8FZW	STAT3_HUMAN	Inhibitor	[11]

Acitretin Interacts with 14 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[12]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Activity	[13]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[14]
Retinoic acid receptor RXR-alpha (RXRA)	OTP1TBDM	RXRA_HUMAN	Affects Binding	[15]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[16]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[13]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Expression	[16]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Expression	[16]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[17]
Tumor necrosis factor ligand superfamily member 6 (FASLG)	OTZARCHH	TNFL6_HUMAN	Increases Expression	[13]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[13]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[14]
FAS-associated death domain protein (FADD)	OTV7GFHH	FADD_HUMAN	Increases Expression	[13]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[13]

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] 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: 4329).
• [3] Triamterene 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: 7598).
• [5] Effects of the serine/threonine kinase SGK1 on the epithelial Na(+) channel (ENaC) and CFTR: implications for cystic fibrosis. Cell Physiol Biochem. 2001;11(4):209-18.
• [6] Identification of novel substrates and structure-activity relationship of cellular uptake mediated by human organic cation transporters 1 and 2. J Med Chem. 2013 Sep 26;56(18):7232-42.
• [7] Rate-limiting biotransformation of triamterene is mediated by CYP1A2. Int J Clin Pharmacol Ther. 2005 Jul;43(7):327-34.
• [8] Identification of chemical compounds that induce HIF-1alpha activity. Toxicol Sci. 2009 Nov;112(1):153-63.
• [9] Identification of environmental chemicals that activate p53 signaling after in vitro metabolic activation. Arch Toxicol. 2022 Jul;96(7):1975-1987. doi: 10.1007/s00204-022-03291-5. Epub 2022 Apr 18.
• [10] Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study. Environ Health Perspect. 2015 May;123(5):458-66. doi: 10.1289/ehp.1408775. Epub 2015 Jan 13.
• [11] Effects of acitretin on the expression of signaling pathway-related genes in epidermal squamous-cell carcinoma cells. Zhonghua Zhong Liu Za Zhi. 2006 Jan;28(1):21-4.
• [12] 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.
• [13] Acitretin induces apoptosis through CD95 signalling pathway in human cutaneous squamous cell carcinoma cell line SCL-1. J Cell Mol Med. 2009 Sep;13(9A):2888-98. doi: 10.1111/j.1582-4934.2008.00397.x. Epub 2009 Jun 20.
• [14] [Effects of all-trans-retinoic acid, acitretin and tazarotene on apoptosis and Bax/Bcl-2 expressions of human melanoma cells A375 and the significance]. Di Yi Jun Yi Da Xue Xue Bao. 2005 Aug;25(8):972-4, 978.
• [15] Limited Chemical Structural Diversity Found to Modulate Thyroid Hormone Receptor in the Tox21 Chemical Library. Environ Health Perspect. 2019 Sep;127(9):97009. doi: 10.1289/EHP5314. Epub 2019 Sep 30.
• [16] [Acitretin induces apoptosis and changes of relative signaling pathway in epidermoid carcinoma cell line A431]. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2006 Mar;35(2):182-8. doi: 10.3785/j.issn.1008-9292.2006.02.013.
• [17] Effects of ATRA, acitretin and tazarotene on growth and apoptosis of Tca8113 cells. J Huazhong Univ Sci Technolog Med Sci. 2005;25(4):393-6. doi: 10.1007/BF02828205.