Details of the Drug Combination

General Information of Drug Combination (ID: DCLCHBJ)

• Drug Combination Name: Tiagabine + Cilostazol
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Tiagabine (DMKSQG0): Small molecular drug
  Cilostazol (DMZMSCT): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 10.05
  Bliss Independence Score: 10.05
  Loewe Additivity Score: 12.17
  LHighest Single Agent (HSA) Score: 12.18

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Tiagabine

Disease Entry	ICD 11	Status	REF
Epilepsy	8A60-8A68	Approved	[2]
Anxiety disorder	6B00-6B0Z	Phase 2	[2]

Tiagabine Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Gamma-aminobutyric acid uptake (GABAU)	TTV9MQG	NOUNIPROTAC	Inhibitor	[4]
GABA transporter GAT-1 (SLC6A1)	TTPRKM0	SC6A1_HUMAN	Inhibitor	[5]

Tiagabine Interacts with 2 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]

Tiagabine Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Decreases Activity	[8]
Sodium- and chloride-dependent GABA transporter 1 (SLC6A1)	OTLCJJF3	SC6A1_HUMAN	Decreases Activity	[9]

Indication(s) of Cilostazol

Disease Entry	ICD 11	Status	REF
Intermittent claudication	BD40.00	Approved	[3]

Cilostazol Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Phosphodiesterase 3 (PDE3)	TTZCG4L	NOUNIPROTAC	Modulator	[10]
Phosphodiesterase 3A (PDE3A)	TT06AWU	PDE3A_HUMAN	Inhibitor	[11]

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	[12]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[13]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[12]

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	[14]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[14]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[14]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[14]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[14]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[14]

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	[15]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Response To Substance	[16]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[17]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[15]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[15]
Proliferating cell nuclear antigen (PCNA)	OTHZ1RIA	PCNA_HUMAN	Decreases Expression	[18]
Cystic fibrosis transmembrane conductance regulator (CFTR)	OT6B22QH	CFTR_HUMAN	Increases Activity	[19]
Cyclin-A2 (CCNA2)	OTPHHYZJ	CCNA2_HUMAN	Decreases Expression	[18]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Increases Expression	[15]
Nitric oxide synthase 3 (NOS3)	OTLDT7NR	NOS3_HUMAN	Increases Phosphorylation	[20]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Increases Phosphorylation	[20]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Increases Activity	[16]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[17]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[15]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[21]
Transcription factor E2F1 (E2F1)	OTLKYBBC	E2F1_HUMAN	Decreases Expression	[18]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[21]
Transcription factor E2F2 (E2F2)	OTO75RM7	E2F2_HUMAN	Decreases Expression	[18]
Nuclear factor erythroid 2-related factor 2 (NFE2L2)	OT0HENJ5	NF2L2_HUMAN	Increases Expression	[15]
NAD-dependent protein deacetylase sirtuin-1 (SIRT1)	OTAYZMOY	SIR1_HUMAN	Increases Expression	[20]

References

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• [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: 4818).
• [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: 7148).
• [4] Glutamate- and GABA-based CNS therapeutics. Curr Opin Pharmacol. 2006 Feb;6(1):7-17.
• [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. (Target id: 929).
• [6] Enzyme induction and inhibition by new antiepileptic drugs: a review of human studies. Fundam Clin Pharmacol. 2000 Jul-Aug;14(4):301-19.
• [7] Actual and Predicted Pharmacokinetic Interactions Between Anticonvulsants and Antiretrovirals.
• [8] Inhibition of human aromatase complex (CYP19) by antiepileptic drugs. Toxicol In Vitro. 2008 Feb;22(1):146-53.
• [9] GABA transporter deficiency causes tremor, ataxia, nervousness, and increased GABA-induced tonic conductance in cerebellum. J Neurosci. 2005 Mar 23;25(12):3234-45. doi: 10.1523/JNEUROSCI.3364-04.2005.
• [10] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Effects of CYP3A inhibition on the metabolism of cilostazol. Clin Pharmacokinet. 1999;37 Suppl 2:61-8.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.