Details of the Drug Combination

General Information of Drug Combination (ID: DCD45QD)

• Drug Combination Name: Trifluoperazine + Methylene blue
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Trifluoperazine (DMKBYWI): Small molecular drug
  Methylene blue (DMJAPE7): N.A.
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 3
  Bliss Independence Score: 3
  Loewe Additivity Score: 3.83
  LHighest Single Agent (HSA) Score: 3.85

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Trifluoperazine

Disease Entry	ICD 11	Status	REF
Anxiety	N.A.	Approved	[2]
Schizophrenia	6A20	Approved	[3]

Trifluoperazine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Calmodulin (CALM)	TTV3NH6	CALM1_HUMAN; CALM2_HUMAN; CALM3_HUMAN	Inhibitor	[7]

Trifluoperazine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[8]

Trifluoperazine Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[9]
Dimethylaniline oxidase 2 (FMO2)	DEIASEZ	FMO2_HUMAN	Metabolism	[10]

Trifluoperazine Interacts with 12 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Flavin-containing monooxygenase 2 (FMO2)	OTUJUL9S	FMO2_HUMAN	Increases Oxidation	[10]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Activity	[11]
E3 ubiquitin-protein ligase parkin (PRKN)	OTJBN41W	PRKN_HUMAN	Affects Localization	[12]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Increases Expression	[13]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[14]
Serine/threonine-protein kinase mTOR (MTOR)	OTHH8KU7	MTOR_HUMAN	Decreases Phosphorylation	[15]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[14]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Decreases Expression	[16]
Stonin-2 (STON2)	OT01JHHE	STON2_HUMAN	Decreases Expression	[15]
D(3) dopamine receptor (DRD3)	OT0OFFKB	DRD3_HUMAN	Increases ADR	[17]
D(4) dopamine receptor (DRD4)	OTAJTO7N	DRD4_HUMAN	Increases ADR	[17]
D(2) dopamine receptor (DRD2)	OTBLXKEG	DRD2_HUMAN	Increases ADR	[17]

Indication(s) of Methylene blue

Disease Entry	ICD 11	Status	REF
Acquired methemoglobinemia	3A93	Approved	[4]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[5]

Methylene blue Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Monoamine oxidase (MAO)	TT32XQJ	NOUNIPROTAC	.	[18]
Guanylate cyclase (GC)	TT6HPVC	NOUNIPROTAC	Inhibitor	[19]

Methylene blue Interacts with 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Amine oxidase B (MAOB)	OTTDFM1O	AOFB_HUMAN	Decreases Activity	[20]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Affects Activity	[21]
Microtubule-associated protein tau (MAPT)	OTMTP2Z7	TAU_HUMAN	Increases Expression	[22]
Glucose-6-phosphate 1-dehydrogenase (G6PD)	OT300SMK	G6PD_HUMAN	Increases Activity	[23]
Acetylcholinesterase (ACHE)	OT2H8HG6	ACES_HUMAN	Decreases Activity	[24]
6-phosphogluconate dehydrogenase, decarboxylating (PGD)	OTVG296F	6PGD_HUMAN	Increases Activity	[23]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases ADR	[17]

References

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• [2] Trifluoperazine FDA Label
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [4] Recombinant Plasmodium falciparum glutathione reductase is inhibited by the antimalarial dye methylene blue. FEBS Lett. 1998 Feb 6;422(3):311-4.
• [5] ClinicalTrials.gov (NCT04370288) Clinical Application of Methylene Blue for Treatment of Covid-19 Patients. U.S. National Institutes of Health.
• [6] Assessment of the inhibition potential of Licochalcone A against human UDP-glucuronosyltransferases. Food Chem Toxicol. 2016 Apr;90:112-22.
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• [8] Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
• [9] Psychotropic Medications Metabolized by Cytochromes P450 (CYP) 1A2 Enzyme and Relevant Drug Interactions: Review of Articles
• [10] Human FMO2-based microbial whole-cell catalysts for drug metabolite synthesis. Microb Cell Fact. 2015 Jun 12;14:82.
• [11] Characterization of the ATPase activity of the Mr 170,000 to 180,000 membrane glycoprotein (P-glycoprotein) associated with multidrug resistance in K562/ADM cells. Cancer Res. 1988 Sep 1;48(17):4926-32.
• [12] Rescue of Pink1 Deficiency by Stress-Dependent Activation of Autophagy. Cell Chem Biol. 2017 Apr 20;24(4):471-480.e4. doi: 10.1016/j.chembiol.2017.03.005. Epub 2017 Mar 30.
• [13] Association of high prolactin levels and neuroleptics immediately postpartum. J Neuropsychiatry Clin Neurosci. 1990 Winter;2(1):115. doi: 10.1176/jnp.2.1.115b.
• [14] Molecular mechanism of trifluoperazine induces apoptosis in human A549 lung adenocarcinoma cell lines. Mol Med Rep. 2009 Sep-Oct;2(5):811-7. doi: 10.3892/mmr_00000177.
• [15] Stonin 2 activates lysosomal-mTOR axis for cell survival in oral cancer. Toxicol In Vitro. 2023 Apr;88:105561. doi: 10.1016/j.tiv.2023.105561. Epub 2023 Jan 23.
• [16] Role of TRP channels and NCX in mediating hypoxia-induced [Ca(2+)](i) elevation in PC12 cells. Respir Physiol Neurobiol. 2008 Dec 31;164(3):386-93. doi: 10.1016/j.resp.2008.09.002. Epub 2008 Sep 7.
• [17] 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.
• [18] Photoluminescence of CdTe nanocrystals modulated by methylene blue and DNA. A label-free luminescent signaling nanohybrid platform. Phys Chem Chem Phys. 2009 Jul 7;11(25):5062-9.
• [19] Curcumin ameliorates high glucose-induced acute vascular endothelial dysfunction in rat thoracic aorta. Clin Exp Pharmacol Physiol. 2009 Dec;36(12):1177-82.
• [20] Inhibition of the bioactivation of the neurotoxin MPTP by antioxidants, redox agents and monoamine oxidase inhibitors. Food Chem Toxicol. 2011 Aug;49(8):1773-81.
• [21] Identification of environmental chemicals that activate p53 signaling after in vitro metabolic activation. Arch Toxicol. 2022 Jul;96(7):1975-1987. doi: 10.1007/s00204-022-03291-5. Epub 2022 Apr 18.
• [22] Pharmacologic reductions of total tau levels; implications for the role of microtubule dynamics in regulating tau expression. Mol Neurodegener. 2006 Jul 26;1:6. doi: 10.1186/1750-1326-1-6.
• [23] Defenses against oxidation in human erythrocytes: role of glutathione reductase in the activation of glucose decarboxylation by hemolytic drugs. J Lab Clin Med. 1991 Apr;117(4):325-31.
• [24] Profiling the Tox21 Chemical Collection for Acetylcholinesterase Inhibition. Environ Health Perspect. 2021 Apr;129(4):47008. doi: 10.1289/EHP6993. Epub 2021 Apr 12.