Details of the Drug Combination

General Information of Drug Combination (ID: DC1ESK3)

• Drug Combination Name: Digitoxin + Estramustine
• Indication: Malignant melanoma; Status: Investigative [1]
• Component Drugs:
  Digitoxin (DMWVIGP): Small molecular drug
  Estramustine (DMWTAOI): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: UACC62
  Zero Interaction Potency (ZIP) Score: 0.47
  Bliss Independence Score: 2.81
  Loewe Additivity Score: 3.72
  LHighest Single Agent (HSA) Score: 6.01

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Digitoxin

Disease Entry	ICD 11	Status	REF
Arrhythmia	BC9Z	Approved	[2]
Congestive cardiac insufficiency	BD1Z	Approved	[2]
Heart failure	BD10-BD13	Approved	[2]

Digitoxin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Sodium/potassium-transporting ATPase (SPT ATPase)	TTQ38E9	AT1A1_HUMAN; AT1A2_HUMAN; AT1A3_HUMAN; AT1B1_HUMAN; AT1B2_HUMAN; AT1B3_HUMAN	Inhibitor	[4]

Digitoxin 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]

Digitoxin Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[6]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[7]
Sulfotransferase 1A1 (SULT1A1)	DEYWLRK	ST1A1_HUMAN	Metabolism	[8]

Digitoxin Interacts with 22 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Transport	[9]
Nitric oxide synthase 3 (NOS3)	OTLDT7NR	NOS3_HUMAN	Increases Activity	[10]
Serine/threonine-protein kinase Chk1 (CHEK1)	OTTTI622	CHK1_HUMAN	Decreases Expression	[11]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[11]
Serine/threonine-protein kinase Chk2 (CHEK2)	OT8ZPCNS	CHK2_HUMAN	Decreases Expression	[11]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Decreases Expression	[11]
Cyclin-dependent kinase 1 (CDK1)	OTW1SC2N	CDK1_HUMAN	Decreases Expression	[11]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Decreases Secretion	[12]
G2/mitotic-specific cyclin-B1 (CCNB1)	OT19S7E5	CCNB1_HUMAN	Decreases Expression	[11]
Ribosomal protein S6 kinase beta-1 (RPS6KB1)	OTAELNGX	KS6B1_HUMAN	Decreases Phosphorylation	[13]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[13]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Decreases Phosphorylation	[12]
Tyrosine-protein phosphatase non-receptor type 6 (PTPN6)	OT33XNZM	PTN6_HUMAN	Increases Expression	[13]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Decreases Expression	[11]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Decreases Expression	[11]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Decreases Expression	[11]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Cleavage	[11]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN)	OTOWDUNT	PTEN_HUMAN	Increases Expression	[13]
Cytochrome c (CYCS)	OTBFALJD	CYC_HUMAN	Increases Expression	[11]
Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1)	OTHBQVD5	4EBP1_HUMAN	Decreases Phosphorylation	[13]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Cleavage	[11]
E3 SUMO-protein ligase PIAS3 (PIAS3)	OT3TWH9R	PIAS3_HUMAN	Increases Expression	[13]

Indication(s) of Estramustine

Disease Entry	ICD 11	Status	REF
Prostate cancer	2C82.0	Approved	[3]

Estramustine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Estramustine binding protein (EMBP)	TTSBFYK	NOUNIPROTAC	Binder	[14]

Estramustine Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[15]

Estramustine Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Keratin, type I cytoskeletal 18 (KRT18)	OTVLQFIP	K1C18_HUMAN	Increases Expression	[16]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Increases Phosphorylation	[17]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adult acute myeloid leukemia	DCGFAYN	HL-60(TB)	Investigative	[1]
Large cell lung carcinoma	DCPHULZ	NCI-H460	Investigative	[1]
Minimally invasive lung adenocarcinoma	DCCHLJZ	NCI-H322M	Investigative	[1]
Breast adenocarcinoma	DCVSXTY	MDA-MB-468	Investigative	[18]

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: 6782).
• [3] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [4] Treatment of congestive heart failure--current status of use of digitoxin. Eur J Clin Invest. 2001;31 Suppl 2:10-7.
• [5] The association of ABCB1 polymorphisms and elevated serum digitoxin concentrations in geriatric patients. Eur J Clin Pharmacol. 2008 Apr;64(4):367-72.
• [6] Species differences in the toxicity and cytochrome P450 IIIA-dependent metabolism of digitoxin. Mol Pharmacol. 1991 Nov;40(5):859-67.
• [7] Use of a human liver microsome bank in drug glucuronidation studies. Toxicol In Vitro. 1991;5(5-6):559-62.
• [8] Hydroxysteroid sulfotransferase and a specific UDP-glucuronosyltransferase are involved in the metabolism of digitoxin in man. Naunyn Schmiedebergs Arch Pharmacol. 1992 Aug;346(2):226-33.
• [9] Heterogeneous transport of digitalis-like compounds by P-glycoprotein in vesicular and cellular assays. Toxicol In Vitro. 2016 Apr;32:138-45. doi: 10.1016/j.tiv.2015.12.009. Epub 2015 Dec 17.
• [10] Digitoxin elicits anti-inflammatory and vasoprotective properties in endothelial cells: Therapeutic implications for the treatment of atherosclerosis? Atherosclerosis. 2009 Oct;206(2):390-6.
• [11] Digitoxin and a synthetic monosaccharide analog inhibit cell viability in lung cancer cells. Toxicol Appl Pharmacol. 2012 Jan 1;258(1):51-60. doi: 10.1016/j.taap.2011.10.007. Epub 2011 Oct 18.
• [12] Digitoxin mimics gene therapy with CFTR and suppresses hypersecretion of IL-8 from cystic fibrosis lung epithelial cells. Proc Natl Acad Sci U S A. 2004 May 18;101(20):7693-8. doi: 10.1073/pnas.0402030101. Epub 2004 May 10.
• [13] Digitoxin promotes apoptosis and inhibits proliferation and migration by reducing HIF-1 and STAT3 in KRAS mutant human colon cancer cells. Chem Biol Interact. 2022 Jan 5;351:109729. doi: 10.1016/j.cbi.2021.109729. Epub 2021 Oct 28.
• [14] Estramustine binding protein in primary tumours and metastases of malignant melanoma. Melanoma Res. 1994 Dec;4(6):401-5.
• [15] Activity of docetaxel with or without estramustine phosphate versus mitoxantrone in androgen dependent and independent human prostate cancer xenografts. J Urol. 2003 May;169(5):1729-34.
• [16] Docetaxel induces apoptosis in hormone refractory prostate carcinomas during multiple treatment cycles. Br J Cancer. 2006 Jun 5;94(11):1592-8. doi: 10.1038/sj.bjc.6603129.
• [17] Induction of apoptosis by estramustine phosphate mediated by phosphorylation of bcl-2. J Neurooncol. 2001 Aug;54(1):23-9. doi: 10.1023/a:1012566601485.
• [18] Biologically active neutrophil chemokine pattern in tonsillitis.Clin Exp Immunol. 2004 Mar;135(3):511-8. doi: 10.1111/j.1365-2249.2003.02390.x.