Details of the Drug Combination

General Information of Drug Combination (ID: DCHHJT6)

• Drug Combination Name: Busulfan + Methylene blue
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Busulfan (DMXYJ9C): Small molecular drug
  Methylene blue (DMJAPE7): N.A.
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 3.14
  Bliss Independence Score: 3.14
  Loewe Additivity Score: 3.96
  LHighest Single Agent (HSA) Score: 3.96

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Busulfan

Disease Entry	ICD 11	Status	REF
Chronic myelogenous leukaemia	2A20.0	Approved	[2]
Hematologic disease	3C0Z	Approved	[2]
Immunodeficiency	4A00-4A85	Approved	[2]
Leukemia	N.A.	Approved	[2]
Myeloproliferative syndrome	2A22	Approved	[3]
Systemic lupus erythematosus	4A40.0	Approved	[2]
Systemic sclerosis	4A42	Approved	[2]
Neuroblastoma	2D11.2	Investigative	[2]
Retinoblastoma	2D02.2	Investigative	[2]

Busulfan Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Modulator	[7]

Busulfan Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[8]
Glutathione S-transferase alpha-1 (GSTA1)	DE4ZHS1	GSTA1_HUMAN	Metabolism	[9]
Glutathione S-transferase alpha-2 (GSTA2)	DEH49YS	GSTA2_HUMAN	Metabolism	[10]
Glutathione S-transferase pi (GSTP1)	DEK6079	GSTP1_HUMAN	Metabolism	[11]
Microsomal glutathione S-transferase 2 (MGST2)	DE31KMQ	MGST2_HUMAN	Metabolism	[12]
Glutathione S-transferase mu-1 (GSTM1)	DEYZEJA	GSTM1_HUMAN	Metabolism	[11]

Busulfan Interacts with 34 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Glutathione S-transferase P (GSTP1)	OTLP0A0Y	GSTP1_HUMAN	Affects Abundance	[13]
Glutathione S-transferase Mu 1 (GSTM1)	OTSBF2MO	GSTM1_HUMAN	Affects Abundance	[13]
Microsomal glutathione S-transferase 2 (MGST2)	OT4UGTDO	MGST2_HUMAN	Decreases Response To Substance	[12]
Glutathione S-transferase A1 (GSTA1)	OTA7K5XA	GSTA1_HUMAN	Decreases Response To Substance	[14]
Serotransferrin (TF)	OT41PEMS	TRFE_HUMAN	Increases Expression	[15]
Inhibin beta A chain (INHBA)	OTSP64PQ	INHBA_HUMAN	Increases Expression	[15]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Increases Expression	[15]
Antithrombin-III (SERPINC1)	OTDFATG0	ANT3_HUMAN	Affects Expression	[16]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Increases Expression	[17]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases Expression	[17]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[6]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[18]
Plasminogen activator inhibitor 1 (SERPINE1)	OTT0MPQ3	PAI1_HUMAN	Increases Expression	[17]
Thrombospondin-1 (THBS1)	OT0ECWK3	TSP1_HUMAN	Increases Expression	[17]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[19]
Tissue factor pathway inhibitor (TFPI)	OTA0FX16	TFPI1_HUMAN	Decreases Expression	[17]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Phosphorylation	[19]
Cyclic AMP-dependent transcription factor ATF-4 (ATF4)	OTRFV19J	ATF4_HUMAN	Increases Expression	[6]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Increases Expression	[6]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Activity	[20]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Activity	[20]
Aryl hydrocarbon receptor (AHR)	OTFE4EYE	AHR_HUMAN	Increases Expression	[6]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Affects Expression	[6]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[20]
Signal transducer and activator of transcription 1-alpha/beta (STAT1)	OTLMBUZ6	STAT1_HUMAN	Affects Expression	[6]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[21]
Signal transducer and activator of transcription 2 (STAT2)	OTO9G2RZ	STAT2_HUMAN	Decreases Expression	[6]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[19]
Metal regulatory transcription factor 1 (MTF1)	OTJWVLLF	MTF1_HUMAN	Decreases Expression	[6]
Nuclear factor erythroid 2-related factor 2 (NFE2L2)	OT0HENJ5	NF2L2_HUMAN	Increases Expression	[6]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Increases Expression	[6]
Pseudouridylate synthase 7 homolog (PUS7)	OTE5AQHJ	PUS7_HUMAN	Increases Expression	[22]
DNA repair nuclease/redox regulator APEX1 (APEX1)	OT53OI14	APEX1_HUMAN	Increases Response To Substance	[23]
Rho GDP-dissociation inhibitor 1 (ARHGDIA)	OTEXWJDO	GDIR1_HUMAN	Affects Response To Substance	[21]

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	.	[24]
Guanylate cyclase (GC)	TT6HPVC	NOUNIPROTAC	Inhibitor	[25]

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	[26]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Affects Activity	[27]
Microtubule-associated protein tau (MAPT)	OTMTP2Z7	TAU_HUMAN	Increases Expression	[28]
Glucose-6-phosphate 1-dehydrogenase (G6PD)	OT300SMK	G6PD_HUMAN	Increases Activity	[29]
Acetylcholinesterase (ACHE)	OT2H8HG6	ACES_HUMAN	Decreases Activity	[30]
6-phosphogluconate dehydrogenase, decarboxylating (PGD)	OTVG296F	6PGD_HUMAN	Increases Activity	[29]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases ADR	[31]

References

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• [2] Busulfan 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: 7136).
• [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.
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• [11] Busulfan conjugation by glutathione S-transferases alpha, mu, and pi. Drug Metab Dispos. 1996 Sep;24(9):1015-9.
• [12] Overexpression of glutathione-S-transferase, MGSTII, confers resistance to busulfan and melphalan. Cancer Invest. 2005;23(1):19-25.
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• [14] Overexpression of glutathione S-transferase A1-1 in ECV 304 cells protects against busulfan mediated G2-arrest and induces tissue factor expression. Br J Pharmacol. 2002 Dec;137(7):1100-6. doi: 10.1038/sj.bjp.0704972.
• [15] Busulfan induces activin A expression in vitro and in vivo: a possible link to venous occlusive disease. Clin Pharmacol Ther. 2003 Sep;74(3):264-74.
• [16] Decreased incidence of hepatic veno-occlusive disease and fewer hemostatic derangements associated with intravenous busulfan vs oral busulfan in adults conditioned with busulfan + cyclophosphamide for allogeneic bone marrow transplantation. Ann Hematol. 2005 May;84(5):321-30. doi: 10.1007/s00277-004-0982-4. Epub 2004 Dec 4.
• [17] Antineoplastic agent busulfan regulates a network of genes related to coagulation and fibrinolysis. Eur J Clin Pharmacol. 2012 Jun;68(6):923-35. doi: 10.1007/s00228-011-1209-y.
• [18] 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.
• [19] Altered gene expression in busulfan-resistant human myeloid leukemia. Leuk Res. 2008 Nov;32(11):1684-97. doi: 10.1016/j.leukres.2008.01.016. Epub 2008 Mar 12.
• [20] Busulfan selectively induces cellular senescence but not apoptosis in WI38 fibroblasts via a p53-independent but extracellular signal-regulated kinase-p38 mitogen-activated protein kinase-dependent mechanism. J Pharmacol Exp Ther. 2006 Nov;319(2):551-60. doi: 10.1124/jpet.106.107771. Epub 2006 Aug 1.
• [21] Reduced expression of Rho guanine nucleotide dissociation inhibitor-alpha modulates the cytotoxic effect of busulfan in HEK293 cells. Anticancer Drugs. 2007 Mar;18(3):333-40. doi: 10.1097/CAD.0b013e328011fd7f.
• [22] CD34+ derived macrophage and dendritic cells display differential responses to paraquat. Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.
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• [29] 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.
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