Details of the Drug Combination

General Information of Drug Combination (ID: DCA1FJ9)

• Drug Combination Name: Amiloride + Idarubicin
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Amiloride (DMRTSGP): Small molecular drug
  Idarubicin (DMM0XGL): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 17.02
  Bliss Independence Score: 17.02
  Loewe Additivity Score: 25.93
  LHighest Single Agent (HSA) Score: 25.93

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Amiloride

Disease Entry	ICD 11	Status	REF
Congestive heart failure	BD10	Approved	[2]
Edema	MG29	Approved	[3]

Amiloride Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Acid-sensing ion channel 1 (ASIC1)	TTRJYB6	ASIC1_HUMAN	Modulator	[7]

Amiloride Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[8]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[9]

Amiloride Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Diamine oxidase (AOC1)	OTRC220K	AOC1_HUMAN	Decreases Activity	[10]
3-phosphoinositide-dependent protein kinase 1 (PDPK1)	OTT09ZVP	PDPK1_HUMAN	Decreases Phosphorylation	[11]
Dysferlin (DYSF)	OTNSKJU0	DYSF_HUMAN	Decreases Expression	[12]
Urokinase-type plasminogen activator (PLAU)	OTX0QGKK	UROK_HUMAN	Decreases Activity	[13]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Increases Expression	[14]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Increases Expression	[15]
Receptor tyrosine-protein kinase erbB-2 (ERBB2)	OTOAUNCK	ERBB2_HUMAN	Decreases Phosphorylation	[11]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[16]
Myogenic factor 5 (MYF5)	OTTVO2S5	MYF5_HUMAN	Increases Expression	[12]
G2/mitotic-specific cyclin-B1 (CCNB1)	OT19S7E5	CCNB1_HUMAN	Decreases Expression	[17]
Pancreas/duodenum homeobox protein 1 (PDX1)	OTX1DKRA	PDX1_HUMAN	Decreases Uptake	[18]
Serine/threonine-protein phosphatase PP1-alpha catalytic subunit (PPP1CA)	OT7Y43A1	PP1A_HUMAN	Decreases Phosphorylation	[11]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[16]
Multidrug and toxin extrusion protein 1 (SLC47A1)	OTZX0U5Q	S47A1_HUMAN	Decreases Activity	[19]
Glutamate receptor-interacting protein 1 (GRIP1)	OT958HK1	GRIP1_HUMAN	Affects Response To Substance	[20]

Indication(s) of Idarubicin

Disease Entry	ICD 11	Status	REF
Acute myelogenous leukaemia	2A41	Approved	[4]
Acute myeloid leukaemia	2A60	Approved	[5]
Adult acute monocytic leukemia	N.A.	Approved	[4]
Childhood acute megakaryoblastic leukemia	N.A.	Approved	[4]
Leukemia	N.A.	Approved	[4]

Idarubicin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
DNA topoisomerase II (TOP2)	TT0IHXV	TOP2A_HUMAN; TOP2B_HUMAN	Modulator	[7]

Idarubicin Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 1 (ABCC1)	DTSYQGK	MRP1_HUMAN	Substrate	[22]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[23]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[23]

Idarubicin Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[24]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[24]

Idarubicin Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Estrogen receptor (ESR1)	OTKLU61J	ESR1_HUMAN	Decreases Activity	[21]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[25]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Increases Activity	[21]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Increases Expression	[26]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Decreases Activity	[21]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[27]
Peroxisome proliferator-activated receptor delta (PPARD)	OTI4WTOP	PPARD_HUMAN	Decreases Activity	[21]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[28]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Decreases Activity	[21]

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: 2421).
• [3] Amiloride FDA Label
• [4] Idarubicin 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: 7083).
• [6] Reduction of intracellular pH inhibits the expression of VEGF in K562 cells after targeted inhibition of the Na+/H+ exchanger. Leuk Res. 2007 Apr;31(4):507-14. doi: 10.1016/j.leukres.2006.06.015. Epub 2006 Aug 1.
• [7] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [8] Characterization of regulatory mechanisms and states of human organic cation transporter 2. Am J Physiol Cell Physiol. 2006 Jun;290(6):C1521-31.
• [9] 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.
• [10] Diamine oxidase is the amiloride-binding protein and is inhibited by amiloride analogues. J Biol Chem. 1994 Apr 1;269(13):9921-5.
• [11] Role of HER-2/neu signaling in sensitivity to tumor necrosis factor-related apoptosis-inducing ligand: enhancement of TRAIL-mediated apoptosis by amiloride. J Cell Biochem. 2005 Oct 1;96(2):376-89. doi: 10.1002/jcb.20512.
• [12] In vivo and in vitro dysferlin expression in human muscle satellite cells. J Neuropathol Exp Neurol. 2004 Oct;63(10):1104-13. doi: 10.1093/jnen/63.10.1104.
• [13] Amplification of urokinase gene in prostate cancer. Cancer Res. 2001 Jul 15;61(14):5340-4.
• [14] Amiloride, spironolactone, and potassium chloride in thiazide-treated hypertensive patients. Clin Pharmacol Ther. 1980 Apr;27(4):533-43. doi: 10.1038/clpt.1980.75.
• [15] Selection of drugs to test the specificity of the Tg.AC assay by screening for induction of the gadd153 promoter in vitro. Toxicol Sci. 2003 Aug;74(2):260-70. doi: 10.1093/toxsci/kfg113. Epub 2003 May 2.
• [16] 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.
• [17] Reduction in the radiation-induced late S phase and G2 blocks in HL-60 cell populations by amiloride, an efficient inhibitor of the Na+/H+ transporter. Cancer Res. 1998 Feb 1;58(3):413-20.
• [18] PDX-1 protein is internalized by lipid raft-dependent macropinocytosis. Cell Transplant. 2005;14(9):637-45. doi: 10.3727/000000005783982648.
• [19] Molecular identification and functional characterization of rat multidrug and toxin extrusion type transporter 1 as an organic cation/H+ antiporter in the kidney. Drug Metab Dispos. 2006 Nov;34(11):1868-74. doi: 10.1124/dmd.106.010876. Epub 2006 Aug 23.
• [20] 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.
• [21] Quantitative high-throughput profiling of environmental chemicals and drugs that modulate farnesoid X receptor. Sci Rep. 2014 Sep 26;4:6437. doi: 10.1038/srep06437.
• [22] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [23] Amonafide L-malate is not a substrate for multidrug resistance proteins in secondary acute myeloid leukemia. Leukemia. 2008 Nov;22(11):2110-5.
• [24] In vitro evaluation of cytochrome P450-mediated drug interactions between cytarabine, idarubicin, itraconazole and caspofungin. Hematology. 2004 Jun;9(3):217-21.
• [25] A Quantitative Approach to Screen for Nephrotoxic Compounds In Vitro. J Am Soc Nephrol. 2016 Apr;27(4):1015-28. doi: 10.1681/ASN.2015010060. Epub 2015 Aug 10.
• [26] The use of biochemical markers in cardiotoxicity monitoring in patients treated for leukemia. Neoplasma. 2005;52(5):430-4.
• [27] The induction of apoptosis by daunorubicin and idarubicin in human trisomic and diabetic fibroblasts. Cell Mol Biol Lett. 2008;13(2):182-94. doi: 10.2478/s11658-007-0045-7. Epub 2008 Apr 10.
• [28] Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model. Toxicol Sci. 2013 Dec;136(2):581-94. doi: 10.1093/toxsci/kft205. Epub 2013 Sep 19.