Details of the Drug Combination

General Information of Drug Combination (ID: DCY92KC)

• Drug Combination Name: Sumatriptan + Cilostazol
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Sumatriptan (DMVYXR8): Small molecular drug
  Cilostazol (DMZMSCT): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 3.01
  Bliss Independence Score: 3.01
  Loewe Additivity Score: 18.17
  LHighest Single Agent (HSA) Score: 18.18

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Sumatriptan

Disease Entry	ICD 11	Status	REF
Cluster headache	8A81.0	Approved	[2]
Migraine	8A80	Approved	[3]
Migraine disorder	N.A.	Approved	[2]

Sumatriptan Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
5-HT 1D receptor (HTR1D)	TT6MSOK	5HT1D_HUMAN	Agonist	[5]

Sumatriptan Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[6]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[7]

Sumatriptan Interacts with 5 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Nuclear receptor subfamily 0 group B member 2 (NR0B2)	OT7UVICX	NR0B2_HUMAN	Decreases Expression	[8]
Pro-opiomelanocortin (POMC)	OTV41F7T	COLI_HUMAN	Decreases Expression	[9]
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (GNB3)	OTA6HYBA	GBB3_HUMAN	Increases Response	[10]
5-hydroxytryptamine receptor 1F (HTR1F)	OTALAXPA	5HT1F_HUMAN	Increases ADR	[11]
Calcitonin gene-related peptide 1 (CALCA)	OTQSXM9Z	CALCA_HUMAN	Increases ADR	[11]

Indication(s) of Cilostazol

Disease Entry	ICD 11	Status	REF
Intermittent claudication	BD40.00	Approved	[4]

Cilostazol Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Phosphodiesterase 3 (PDE3)	TTZCG4L	NOUNIPROTAC	Modulator	[12]
Phosphodiesterase 3A (PDE3A)	TT06AWU	PDE3A_HUMAN	Inhibitor	[13]

Cilostazol Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[14]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[15]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[14]

Cilostazol Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[16]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[16]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[16]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[16]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[16]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[16]

Cilostazol Interacts with 20 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Apoptosis-inducing factor 1, mitochondrial (AIFM1)	OTKPWB7Q	AIFM1_HUMAN	Increases Localization	[17]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Response To Substance	[18]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[19]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[17]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[17]
Proliferating cell nuclear antigen (PCNA)	OTHZ1RIA	PCNA_HUMAN	Decreases Expression	[20]
Cystic fibrosis transmembrane conductance regulator (CFTR)	OT6B22QH	CFTR_HUMAN	Increases Activity	[21]
Cyclin-A2 (CCNA2)	OTPHHYZJ	CCNA2_HUMAN	Decreases Expression	[20]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Increases Expression	[17]
Nitric oxide synthase 3 (NOS3)	OTLDT7NR	NOS3_HUMAN	Increases Phosphorylation	[22]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Increases Phosphorylation	[22]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Increases Activity	[18]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[19]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[17]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[23]
Transcription factor E2F1 (E2F1)	OTLKYBBC	E2F1_HUMAN	Decreases Expression	[20]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[23]
Transcription factor E2F2 (E2F2)	OTO75RM7	E2F2_HUMAN	Decreases Expression	[20]
Nuclear factor erythroid 2-related factor 2 (NFE2L2)	OT0HENJ5	NF2L2_HUMAN	Increases Expression	[17]
NAD-dependent protein deacetylase sirtuin-1 (SIRT1)	OTAYZMOY	SIR1_HUMAN	Increases Expression	[22]

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] Sumatriptan FDA Label
• [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: 54).
• [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: 7148).
• [5] Irritable bowel syndrome: new agents targeting serotonin receptor subtypes. Drugs. 2001;61(3):317-32.
• [6] HT29-MTX and Caco-2/TC7 monolayers as predictive models for human intestinal absorption: role of the mucus layer. J Pharm Sci. 2001 Oct;90(10):1608-19. Comparative Study
• [7] 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.
• [8] A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system. Toxicol Sci. 2005 Feb;83(2):282-92.
• [9] The effects of oral sumatriptan, a 5-HT1 receptor agonist, on circulating ACTH and cortisol concentrations in man. Br J Clin Pharmacol. 1995 Apr;39(4):389-95. doi: 10.1111/j.1365-2125.1995.tb04467.x.
• [10] G protein beta3 polymorphism and triptan response in cluster headache. Clin Pharmacol Ther. 2007 Oct;82(4):396-401. doi: 10.1038/sj.clpt.6100159. Epub 2007 Mar 14.
• [11] 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.
• [12] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [13] A new generation of phosphodiesterase inhibitors: multiple molecular forms of phosphodiesterase and the potential for drug selectivity. J Med Chem. 1985 May;28(5):537-45.
• [14] Organic Anion-Transporting Polypeptide and Efflux Transporter-Mediated Hepatic Uptake and Biliary Excretion of Cilostazol and Its Metabolites in Rats and Humans. J Pharm Sci. 2017 Sep;106(9):2515-2523.
• [15] Aspirin and probenecid inhibit organic anion transporter 3-mediated renal uptake of cilostazol and probenecid induces metabolism of cilostazol in the rat. Drug Metab Dispos. 2014 Jun;42(6):996-1007.
• [16] Effects of CYP3A inhibition on the metabolism of cilostazol. Clin Pharmacokinet. 1999;37 Suppl 2:61-8.
• [17] Cilostazol enhances apoptosis of synovial cells from rheumatoid arthritis patients with inhibition of cytokine formation via Nrf2-linked heme oxygenase 1 induction. Arthritis Rheum. 2010 Mar;62(3):732-41. doi: 10.1002/art.27291.
• [18] HO-1 Induced by Cilostazol Protects Against TNF--associated Cytotoxicity via a PPAR--dependent Pathway in Human Endothelial Cells. Korean J Physiol Pharmacol. 2011 Apr;15(2):83-8. doi: 10.4196/kjpp.2011.15.2.83. Epub 2011 Apr 30.
• [19] Cyclic AMP inhibited proliferation of human aortic vascular smooth muscle cells, accompanied by induction of p53 and p21. Hypertension. 2000 Jan;35(1 Pt 2):237-43. doi: 10.1161/01.hyp.35.1.237.
• [20] Cilostazol inhibits vascular smooth muscle cell growth by downregulation of the transcription factor E2F. Hypertension. 2005 Apr;45(4):552-6. doi: 10.1161/01.HYP.0000158263.64320.eb. Epub 2005 Feb 21.
• [21] Adenosine receptors and phosphodiesterase inhibitors stimulate Cl- secretion in Calu-3 cells. Am J Respir Cell Mol Biol. 2003 Sep;29(3 Pt 1):410-8. doi: 10.1165/rcmb.2002-0247OC. Epub 2003 Apr 24.
• [22] Cilostazol inhibits oxidative stress-induced premature senescence via upregulation of Sirt1 in human endothelial cells. Arterioscler Thromb Vasc Biol. 2008 Sep;28(9):1634-9. doi: 10.1161/ATVBAHA.108.164368. Epub 2008 Jun 12.
• [23] Inhibiting AKT signaling pathway with cilostazol and meloxicam synergism for suppressing K562 cells in vitro. J Biochem Mol Toxicol. 2022 Nov;36(11):e23185. doi: 10.1002/jbt.23185. Epub 2022 Aug 3.