Details of the Drug Combination

General Information of Drug Combination (ID: DC3K4Y3)

• Drug Combination Name: Anastrozole + Digitoxin
• Indication: Minimally invasive lung adenocarcinoma; Status: Investigative [1]
• Component Drugs:
  Anastrozole (DMNP60F): Small molecular drug
  Digitoxin (DMWVIGP): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: NCI-H322M
  Zero Interaction Potency (ZIP) Score: 7.95
  Bliss Independence Score: 4.82
  Loewe Additivity Score: 3.73
  LHighest Single Agent (HSA) Score: 3.52

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Anastrozole

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Approved	[2]
Estrogen-receptor positive breast cancer	N.A.	Approved	[3]
Obesity	5B81	Approved	[3]

Anastrozole Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Aromatase (CYP19A1)	TTSZLWK	CP19A_HUMAN	Inhibitor	[5]

Anastrozole Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Putative sodium-coupled neutral amino acid transporter 7 (SLC38A7)	DT2EGUN	S38A7_HUMAN	Substrate	[6]

Anastrozole Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[7]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[7]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[7]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[7]
UDP-glucuronosyltransferase 1A3 (UGT1A3)	DEF2WXN	UD13_HUMAN	Metabolism	[7]

Anastrozole Interacts with 6 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Adenylate kinase isoenzyme 1 (AK1)	OT614AR3	KAD1_HUMAN	Increases ADR	[8]
Progesterone receptor (PGR)	OT0FZ3QE	PRGR_HUMAN	Decreases Expression	[9]
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Decreases Activity	[10]
NADPH--cytochrome P450 reductase (POR)	OTVIDOCH	NCPR_HUMAN	Decreases Activity	[11]
Gap junction alpha-1 protein (GJA1)	OTT94MKL	CXA1_HUMAN	Decreases Expression	[12]
Proliferation marker protein Ki-67 (MKI67)	OTA8N1QI	KI67_HUMAN	Decreases Expression	[13]

Indication(s) of Digitoxin

Disease Entry	ICD 11	Status	REF
Arrhythmia	BC9Z	Approved	[4]
Congestive cardiac insufficiency	BD1Z	Approved	[4]
Heart failure	BD10-BD13	Approved	[4]

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	[14]

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	[15]

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	[16]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[17]
Sulfotransferase 1A1 (SULT1A1)	DEYWLRK	ST1A1_HUMAN	Metabolism	[18]

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	[19]
Nitric oxide synthase 3 (NOS3)	OTLDT7NR	NOS3_HUMAN	Increases Activity	[20]
Serine/threonine-protein kinase Chk1 (CHEK1)	OTTTI622	CHK1_HUMAN	Decreases Expression	[21]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[21]
Serine/threonine-protein kinase Chk2 (CHEK2)	OT8ZPCNS	CHK2_HUMAN	Decreases Expression	[21]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Decreases Expression	[21]
Cyclin-dependent kinase 1 (CDK1)	OTW1SC2N	CDK1_HUMAN	Decreases Expression	[21]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Decreases Secretion	[22]
G2/mitotic-specific cyclin-B1 (CCNB1)	OT19S7E5	CCNB1_HUMAN	Decreases Expression	[21]
Ribosomal protein S6 kinase beta-1 (RPS6KB1)	OTAELNGX	KS6B1_HUMAN	Decreases Phosphorylation	[23]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[23]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Decreases Phosphorylation	[22]
Tyrosine-protein phosphatase non-receptor type 6 (PTPN6)	OT33XNZM	PTN6_HUMAN	Increases Expression	[23]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Decreases Expression	[21]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Decreases Expression	[21]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Decreases Expression	[21]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Cleavage	[21]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN)	OTOWDUNT	PTEN_HUMAN	Increases Expression	[23]
Cytochrome c (CYCS)	OTBFALJD	CYC_HUMAN	Increases Expression	[21]
Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1)	OTHBQVD5	4EBP1_HUMAN	Decreases Phosphorylation	[23]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Cleavage	[21]
E3 SUMO-protein ligase PIAS3 (PIAS3)	OT3TWH9R	PIAS3_HUMAN	Increases Expression	[23]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adenocarcinoma	DCYH82Y	DU-145	Investigative	[1]
Amelanotic melanoma	DCZ76CW	MDA-MB-435	Investigative	[1]
Chronic myelogenous leukemia	DC1OGW8	K-562	Investigative	[1]
Cutaneous melanoma	DCZ2SH5	SK-MEL-5	Investigative	[1]
Glioma	DCBLDDE	SF-268	Investigative	[1]
Large cell lung carcinoma	DC2WRDX	NCI-H460	Investigative	[1]
Mixed endometrioid and clear cell carcinoma	DCHK22O	IGROV1	Investigative	[1]
Ovarian serous cystadenocarcinoma	DCNMBQF	SK-OV-3	Investigative	[1]
Carcinoma	DCEOTIC	MCF7	Investigative	[24]

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: 5137).
• [3] Anastrozole 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: 6782).
• [5] Effective aromatase inhibition by anastrozole in a patient with gonadotropin-independent precocious puberty in McCune-Albright syndrome. J Pediatr Endocrinol Metab. 2002;15 Suppl 3:945-8.
• [6] Anastrozole Aromatase Inhibitor Plasma Drug Concentration Genome-Wide Association Study: Functional Epistatic Interaction Between SLC38A7 and ALPPL2. Clin Pharmacol Ther. 2019 Jan 16.
• [7] In vitro and in vivo oxidative metabolism and glucuronidation of anastrozole. Br J Clin Pharmacol. 2010 Dec;70(6):854-69.
• [8] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [9] Aromatase inhibitors: cellular and molecular effects. J Steroid Biochem Mol Biol. 2005 May;95(1-5):83-9. doi: 10.1016/j.jsbmb.2005.04.010.
• [10] Aromatase inhibition: translation into a successful therapeutic approach. Clin Cancer Res. 2005 Apr 15;11(8):2809-21. doi: 10.1158/1078-0432.CCR-04-2187.
• [11] Assessment of Five Pesticides as Endocrine-Disrupting Chemicals: Effects on Estrogen Receptors and Aromatase. Int J Environ Res Public Health. 2022 Feb 10;19(4):1959. doi: 10.3390/ijerph19041959.
• [12] Inhibition of estrogen receptor reduces connexin 43 expression in breast cancers. Toxicol Appl Pharmacol. 2018 Jan 1;338:182-190. doi: 10.1016/j.taap.2017.11.020. Epub 2017 Nov 24.
• [13] Biomarker changes during neoadjuvant anastrozole, tamoxifen, or the combination: influence of hormonal status and HER-2 in breast cancer--a study from the IMPACT trialists. J Clin Oncol. 2005 Apr 10;23(11):2477-92. doi: 10.1200/JCO.2005.07.559. Epub 2005 Mar 14.
• [14] Treatment of congestive heart failure--current status of use of digitoxin. Eur J Clin Invest. 2001;31 Suppl 2:10-7.
• [15] The association of ABCB1 polymorphisms and elevated serum digitoxin concentrations in geriatric patients. Eur J Clin Pharmacol. 2008 Apr;64(4):367-72.
• [16] Species differences in the toxicity and cytochrome P450 IIIA-dependent metabolism of digitoxin. Mol Pharmacol. 1991 Nov;40(5):859-67.
• [17] Use of a human liver microsome bank in drug glucuronidation studies. Toxicol In Vitro. 1991;5(5-6):559-62.
• [18] 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.
• [19] 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.
• [20] Digitoxin elicits anti-inflammatory and vasoprotective properties in endothelial cells: Therapeutic implications for the treatment of atherosclerosis? Atherosclerosis. 2009 Oct;206(2):390-6.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] 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.