Details of the Drug Combination

General Information of Drug Combination (ID: DCI75AC)

• Drug Combination Name: Regadenoson + Adenosine
• Indication: Obesity; Status: Phase 1 [1]
• Component Drugs:
  Regadenoson (DM76VHG): Small molecular drug
  Adenosine (DMM2NSK): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Regadenoson

Disease Entry	ICD 11	Status	REF
Radionuclide imaging	N.A.	Approved	[2]

Regadenoson Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adenosine A2a receptor (ADORA2A)	TTM2AOE	AA2AR_HUMAN	Modulator	[4]

Indication(s) of Adenosine

Disease Entry	ICD 11	Status	REF
Paroxysmal supraventricular tachycardia	BC81.Z	Approved	[3]

Adenosine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adenosine A2b receptor (ADORA2B)	TTNE7KG	AA2BR_HUMAN	Modulator	[6]

Adenosine Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 5 (ABCC5)	DTYVM24	MRP5_HUMAN	Substrate	[7]
Equilibrative nucleoside transporter 1 (SLC29A1)	DTXD1TQ	S29A1_HUMAN	Substrate	[8]

Adenosine Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Sulfotransferase 1A1 (SULT1A1)	DEYWLRK	ST1A1_HUMAN	Metabolism	[9]
Adenosine aminohydrolase (ADA)	DEDQHBV	ADA_HUMAN	Metabolism	[10]

Adenosine Interacts with 58 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Equilibrative nucleoside transporter 1 (SLC29A1)	OTLOOZZS	S29A1_HUMAN	Increases Uptake	[11]
L-lactate dehydrogenase A chain (LDHA)	OTN7K4XB	LDHA_HUMAN	Increases ADR	[12]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[13]
Dipeptidyl peptidase 4 (DPP4)	OT16MVL9	DPP4_HUMAN	Decreases Expression	[13]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[13]
Toll-like receptor 4 (TLR4)	OTP7ML3S	TLR4_HUMAN	Increases Expression	[14]
CASP8 and FADD-like apoptosis regulator (CFLAR)	OTX14BAS	CFLAR_HUMAN	Decreases Expression	[15]
Dickkopf-related protein 1 (DKK1)	OTRDLUSP	DKK1_HUMAN	Increases Expression	[16]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Increases Expression	[16]
Pro-epidermal growth factor (EGF)	OTANRJ0L	EGF_HUMAN	Increases Expression	[16]
Protransforming growth factor alpha (TGFA)	OTPD1LL9	TGFA_HUMAN	Increases Secretion	[16]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Increases Expression	[16]
Estrogen receptor (ESR1)	OTKLU61J	ESR1_HUMAN	Increases Expression	[17]
Insulin-like growth factor I (IGF1)	OTIIZR61	IGF1_HUMAN	Affects Expression	[16]
Monocyte differentiation antigen CD14 (CD14)	OT83GJ47	CD14_HUMAN	Increases Expression	[14]
Adenosine receptor A3 (ADORA3)	OTHO1BLK	AA3R_HUMAN	Increases Expression	[5]
Bone morphogenetic protein 2 (BMP2)	OT23T37S	BMP2_HUMAN	Increases Expression	[16]
Bone morphogenetic protein 4 (BMP4)	OTPZMDFH	BMP4_HUMAN	Increases Expression	[16]
Cystic fibrosis transmembrane conductance regulator (CFTR)	OT6B22QH	CFTR_HUMAN	Increases Activity	[18]
Cyclic AMP-responsive element-binding protein 1 (CREB1)	OT1MDLA1	CREB1_HUMAN	Increases Expression	[16]
Ribosomal protein S6 kinase beta-1 (RPS6KB1)	OTAELNGX	KS6B1_HUMAN	Increases Phosphorylation	[16]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Increases Expression	[16]
Adenosine receptor A2a (ADORA2A)	OTVRBZ0I	AA2AR_HUMAN	Affects Binding	[19]
Adenosine receptor A1 (ADORA1)	OTI7X39E	AA1R_HUMAN	Affects Binding	[19]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Increases Expression	[16]
Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2)	OTUE7Z91	MP2K2_HUMAN	Increases Phosphorylation	[16]
Bone morphogenetic protein receptor type-1A (BMPR1A)	OTQOA4ZH	BMR1A_HUMAN	Increases Expression	[16]
Glial cell line-derived neurotrophic factor (GDNF)	OT8ICC4Z	GDNF_HUMAN	Increases Secretion	[16]
Serine/threonine-protein kinase mTOR (MTOR)	OTHH8KU7	MTOR_HUMAN	Increases Phosphorylation	[16]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[20]
Proliferation marker protein Ki-67 (MKI67)	OTA8N1QI	KI67_HUMAN	Affects Expression	[16]
Tumor necrosis factor ligand superfamily member 6 (FASLG)	OTZARCHH	TNFL6_HUMAN	Increases Expression	[21]
Placenta growth factor (PGF)	OT5MF5DJ	PLGF_HUMAN	Increases Secretion	[16]
Glycogen synthase kinase-3 beta (GSK3B)	OTL3L14B	GSK3B_HUMAN	Increases Expression	[16]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[20]
Transforming growth factor beta-2 proprotein (TGFB2)	OTC0TXEP	TGFB2_HUMAN	Increases Expression	[16]
Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1)	OT4Y9NQI	MP2K1_HUMAN	Increases Phosphorylation	[16]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Localization	[20]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[22]
FAS-associated death domain protein (FADD)	OTV7GFHH	FADD_HUMAN	Decreases Expression	[15]
Frizzled-5 (FZD5)	OTXFFY56	FZD5_HUMAN	Increases Expression	[16]
Baculoviral IAP repeat-containing protein 3 (BIRC3)	OT3E95KB	BIRC3_HUMAN	Decreases Expression	[22]
Baculoviral IAP repeat-containing protein 2 (BIRC2)	OTFXFREP	BIRC2_HUMAN	Decreases Expression	[22]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[15]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Increases Expression	[5]
Estrogen receptor beta (ESR2)	OTXNR2WQ	ESR2_HUMAN	Increases Expression	[17]
Frizzled-3 (FZD3)	OTIWDN78	FZD3_HUMAN	Increases Expression	[16]
Diablo IAP-binding mitochondrial protein (DIABLO)	OTHJ9MCZ	DBLOH_HUMAN	Increases Expression	[22]
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A)	OTHCDQ22	PRGC1_HUMAN	Increases Expression	[23]
Lymphoid enhancer-binding factor 1 (LEF1)	OTWS5I5H	LEF1_HUMAN	Increases Expression	[16]
Lymphocyte antigen 96 (LY96)	OTN4HXA2	LY96_HUMAN	Increases Expression	[14]
Mitogen-activated protein kinase 11 (MAPK11)	OT0AS010	MK11_HUMAN	Increases ADR	[12]
Tyrosine-protein phosphatase non-receptor type 12 (PTPN12)	OT5WA666	PTN12_HUMAN	Increases ADR	[12]
Sodium/nucleoside cotransporter 2 (SLC28A2)	OTFYZK8R	S28A2_HUMAN	Increases Transport	[24]
Equilibrative nucleoside transporter 3 (SLC29A3)	OTGLX8XU	S29A3_HUMAN	Affects Transport	[25]
Purine nucleoside phosphorylase (PNP)	OTO5NIJ2	PNPH_HUMAN	Increases ADR	[12]
Equilibrative nucleoside transporter 2 (SLC29A2)	OTUAOB8T	S29A2_HUMAN	Increases Uptake	[26]
Sodium/nucleoside cotransporter 1 (SLC28A1)	OTXWVV9O	S28A1_HUMAN	Affects Transport	[27]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Hypertrophic Cardiomyopathy	DCXADT2	N. A.	Phase 4	[28]

References

• [1] ClinicalTrials.gov (NCT00859833) Effects of Body Mass Index on the Hyperemic Response to Regadenoson
• [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: 5596).
• [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: 2844).
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] Adenosine up-regulates vascular endothelial growth factor in human macrophages. Biochem Biophys Res Commun. 2010 Feb 12;392(3):351-6. doi: 10.1016/j.bbrc.2010.01.023. Epub 2010 Jan 11.
• [6] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [7] Role of MRP4 and MRP5 in biology and chemotherapy. AAPS PharmSci. 2002;4(3):E14.
• [8] Nitric oxide reduces adenosine transporter ENT1 gene (SLC29A1) promoter activity in human fetal endothelium from gestational diabetes. J Cell Physiol. 2006 Aug;208(2):451-60.
• [9] Regulation of sulfate assimilation in plants: 7. Cysteine inactivation of adenosine 5'-phosphosulfate sulfotransferase in Lemna minor L. Plant Physiol. 1978 Mar;61(3):342-7.
• [10] A functional genetic variation of adenosine deaminase affects the duration and intensity of deep sleep in humans. Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15676-81.
• [11] Functional role of the polymorphic 647 T/C variant of ENT1 (SLC29A1) and its association with alcohol withdrawal seizures. PLoS One. 2011 Jan 24;6(1):e16331. doi: 10.1371/journal.pone.0016331.
• [12] 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.
• [13] Adenosine downregulates DPPIV on HT-29 colon cancer cells by stimulating protein tyrosine phosphatase(s) and reducing ERK1/2 activity via a novel pathway. Am J Physiol Cell Physiol. 2006 Sep;291(3):C433-44.
• [14] Adenosine reduces cell surface expression of toll-like receptor 4 and inflammation in response to lipopolysaccharide and matrix products. J Cardiovasc Transl Res. 2011 Dec;4(6):790-800. doi: 10.1007/s12265-011-9279-x. Epub 2011 May 3.
• [15] Intracellularly transported adenosine induces apoptosis in HuH-7 human hepatoma cells by downregulating c-FLIP expression causing caspase-3/-8 activation. Biochem Pharmacol. 2007 May 15;73(10):1665-75. doi: 10.1016/j.bcp.2007.01.020. Epub 2007 Jan 18.
• [16] Adenosine and Cordycepin Accelerate Tissue Remodeling Process through Adenosine Receptor Mediated Wnt/-Catenin Pathway Stimulation by Regulating GSK3b Activity. Int J Mol Sci. 2021 May 25;22(11):5571. doi: 10.3390/ijms22115571.
• [17] Estrogenic Effects of the Extracts from the Chinese Yam (Dioscorea opposite Thunb.) and Its Effective Compounds in Vitro and in Vivo. Molecules. 2018 Jan 23;23(2):11. doi: 10.3390/molecules23020011.
• [18] Activation of airway cl- secretion in human subjects by adenosine. Am J Respir Cell Mol Biol. 2004 Aug;31(2):140-6. doi: 10.1165/rcmb.2004-0012OC. Epub 2004 Mar 23.
• [19] New 2,6,9-trisubstituted adenines as adenosine receptor antagonists: a preliminary SAR profile. Purinergic Signal. 2007 Sep;3(4):339-46. doi: 10.1007/s11302-007-9068-9. Epub 2007 Sep 19.
• [20] Thymidine-dependent attenuation of the mitochondrial apoptotic pathway in adenosine-induced apoptosis of HL-60 cells. J Cancer Res Clin Oncol. 2001 Sep;127(9):570-6. doi: 10.1007/s004320100264.
• [21] Apoptosis induced by nucleosides in the human hepatoma HepG2. World J Gastroenterol. 2005 Oct 28;11(40):6381-4. doi: 10.3748/wjg.v11.i40.6381.
• [22] Adenosine-induced caspase-3 activation by tuning Bcl-XL/DIABLO/IAP expression in HuH-7 human hepatoma cells. Cell Biol Toxicol. 2010 Aug;26(4):319-30. doi: 10.1007/s10565-009-9145-7. Epub 2010 Jan 9.
• [23] A cardiac-specific robotized cellular assay identified families of human ligands as inducers of PGC-1 expression and mitochondrial biogenesis. PLoS One. 2012;7(10):e46753. doi: 10.1371/journal.pone.0046753. Epub 2012 Oct 3.
• [24] Molecular cloning, functional expression and chromosomal localization of a cDNA encoding a human Na+/nucleoside cotransporter (hCNT2) selective for purine nucleosides and uridine. Mol Membr Biol. 1998 Oct-Dec;15(4):203-11. doi: 10.3109/09687689709044322.
• [25] Facilitated mitochondrial import of antiviral and anticancer nucleoside drugs by human equilibrative nucleoside transporter-3. Am J Physiol Gastrointest Liver Physiol. 2009 Apr;296(4):G910-22. doi: 10.1152/ajpgi.90672.2008. Epub 2009 Jan 22.
• [26] Molecular cloning and characterization of a nitrobenzylthioinosine-insensitive (ei) equilibrative nucleoside transporter from human placenta. Biochem J. 1997 Dec 15;328 ( Pt 3)(Pt 3):739-43. doi: 10.1042/bj3280739.
• [27] Molecular cloning and functional expression of cDNAs encoding a human Na+-nucleoside cotransporter (hCNT1). Am J Physiol. 1997 Feb;272(2 Pt 1):C707-14. doi: 10.1152/ajpcell.1997.272.2.C707.
• [28] ClinicalTrials.gov (NCT03249272) Microvascular Dysfunction in Nonischemic Cardiomyopathy: Insights From CMR Assessment of Coronary Flow Reserve