Details of the Drug Combination

General Information of Drug Combination (ID: DCC7CE9)

• Drug Combination Name: Busulfan + Isoniazid
• Indication: Breast adenocarcinoma; Status: Investigative [1]
• Component Drugs:
  Busulfan (DMXYJ9C): Small molecular drug
  Isoniazid (DM5JVS3): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: MDA-MB-468
  Zero Interaction Potency (ZIP) Score: 1.95
  Bliss Independence Score: 4.4
  Loewe Additivity Score: 2.75
  LHighest Single Agent (HSA) Score: 3.74

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 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Serotransferrin (TF)	OT41PEMS	TRFE_HUMAN	Increases Expression	[13]
Antithrombin-III (SERPINC1)	OTDFATG0	ANT3_HUMAN	Affects Expression	[14]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Increases Expression	[15]
Plasminogen activator inhibitor 1 (SERPINE1)	OTT0MPQ3	PAI1_HUMAN	Increases Expression	[15]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[16]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Phosphorylation	[16]
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	[17]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Activity	[17]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[17]
Signal transducer and activator of transcription 2 (STAT2)	OTO9G2RZ	STAT2_HUMAN	Decreases Expression	[6]
Pseudouridylate synthase 7 homolog (PUS7)	OTE5AQHJ	PUS7_HUMAN	Increases Expression	[18]
DNA repair nuclease/redox regulator APEX1 (APEX1)	OT53OI14	APEX1_HUMAN	Increases Response To Substance	[19]
Rho GDP-dissociation inhibitor 1 (ARHGDIA)	OTEXWJDO	GDIR1_HUMAN	Affects Response To Substance	[20]

Indication(s) of Isoniazid

Disease Entry	ICD 11	Status	REF
Latent tuberculosis infection	N.A.	Approved	[4]
Pulmonary tuberculosis	1B10.Z	Approved	[4]
Tuberculosis	1B10-1B1Z	Approved	[5]

Isoniazid Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial Fatty acid synthetase I (Bact inhA)	TTVTX4N	INHA_MYCTU	Inhibitor	[22]

Isoniazid Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[23]
Catalase-peroxidase (katG)	DEAGY5M	KATG_SYNE7	Metabolism	[24]
Arylamine N-acetyltransferase (NAT)	DEXCQTM	A0A3P8LE58_TSUPA	Metabolism	[25]

Isoniazid Interacts with 28 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
N-alpha-acetyltransferase 20 (NAA20)	OTJB0VA6	NAA20_HUMAN	Increases ADR	[26]
Nuclear protein 1 (NUPR1)	OT4FU8C0	NUPR1_HUMAN	Increases Expression	[27]
Inhibin beta E chain (INHBE)	OTOI2NYG	INHBE_HUMAN	Increases Expression	[27]
Protein DEPP1 (DEPP1)	OTB36PHJ	DEPP1_HUMAN	Increases Expression	[27]
Aldo-keto reductase family 1 member B10 (AKR1B10)	OTOA4HTH	AK1BA_HUMAN	Increases Expression	[21]
Interleukin-12 subunit alpha (IL12A)	OTDQT8GI	IL12A_HUMAN	Increases Secretion	[21]
Interleukin-12 subunit beta (IL12B)	OT0JF8A3	IL12B_HUMAN	Increases Secretion	[21]
Sulfiredoxin-1 (SRXN1)	OTYDBO4L	SRXN1_HUMAN	Increases Expression	[21]
Gamma-butyrobetaine dioxygenase (BBOX1)	OTKEX4RK	BODG_HUMAN	Increases Expression	[28]
Sodium/potassium-transporting ATPase subunit beta-1 (ATP1B1)	OTTO6ZP4	AT1B1_HUMAN	Increases Expression	[28]
Amyloid-beta precursor protein (APP)	OTKFD7R4	A4_HUMAN	Increases Expression	[28]
14-3-3 protein sigma (SFN)	OTLJCZ1U	1433S_HUMAN	Decreases Expression	[28]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Decreases Expression	[28]
Claudin-2 (CLDN2)	OTRF3D6Y	CLD2_HUMAN	Increases Expression	[28]
Large neutral amino acids transporter small subunit 1 (SLC7A5)	OT2WPVXD	LAT1_HUMAN	Decreases Expression	[28]
Tribbles homolog 3 (TRIB3)	OTG5OS7X	TRIB3_HUMAN	Increases Expression	[28]
Procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2)	OTKOZRZP	PLOD2_HUMAN	Increases Expression	[29]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[30]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[31]
5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1)	OTQY6ZSF	HEM1_HUMAN	Increases Expression	[32]
Ferrochelatase, mitochondrial (FECH)	OTDWEI6C	HEMH_HUMAN	Decreases Expression	[32]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[33]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[33]
Nuclear respiratory factor 1 (NRF1)	OTOXWNV8	NRF1_HUMAN	Decreases Expression	[34]
Natural cytotoxicity triggering receptor 3 ligand 1 (NCR3LG1)	OT15YWU7	NR3L1_HUMAN	Increases Expression	[35]
PTB-containing, cubilin and LRP1-interacting protein (PID1)	OT5YJ7FI	PCLI1_HUMAN	Increases Expression	[31]
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A)	OTHCDQ22	PRGC1_HUMAN	Decreases Expression	[34]
Arylamine N-acetyltransferase 2 (NAT2)	OTBPDQOY	ARY2_HUMAN	Decreases Acetylation	[36]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adult T acute lymphoblastic leukemia	DCR7R33	MOLT-4	Investigative	[37]

References

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• [2] Busulfan FDA Label
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• [4] Isoniazid FDA Label
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• [7] DNA intrastrand cross-link at the 5'-GA-3' sequence formed by busulfan and its role in the cytotoxic effect. Cancer Sci. 2004 May;95(5):454-8.
• [8] Update: clinically significant cytochrome P-450 drug interactions. Pharmacotherapy. 1998 Jan-Feb;18(1):84-112.
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• [10] Endothelial cells do not express GSTA1: potential relevance to busulfan-mediated endothelial damage during haematopoietic stem cell transplantation. Eur J Haematol. 2008 Apr;80(4):299-302.
• [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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
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• [18] 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.
• [19] Impairment of APE1 function enhances cellular sensitivity to clinically relevant alkylators and antimetabolites. Mol Cancer Res. 2009 Jun;7(6):897-906. doi: 10.1158/1541-7786.MCR-08-0519. Epub 2009 May 26.
• [20] 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.
• [21] Characterization of drug-specific signaling between primary human hepatocytes and immune cells. Toxicol Sci. 2017 Jul 1;158(1):76-89.
• [22] Diversity in enoyl-acyl carrier protein reductases. Cell Mol Life Sci. 2009 May;66(9):1507-17.
• [23] Inhibition of CYP2E1 catalytic activity in vitro by S-adenosyl-L-methionine. Biochem Pharmacol. 2005 Apr 1;69(7):1081-93.
• [24] Crystal structure of the catalase-peroxidase KatG W78F mutant from Synechococcus elongatus PCC7942 in complex with the antitubercular pro-drug isoniazid. FEBS Lett. 2015 Jan 2;589(1):131-7.
• [25] The actinobacterium Tsukamurella paurometabola has a functionally divergent arylamine N-acetyltransferase (NAT) homolog. World J Microbiol Biotechnol. 2019 Oct 31;35(11):174.
• [26] 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.
• [27] Determination of phospholipidosis potential based on gene expression analysis in HepG2 cells. Toxicol Sci. 2007 Mar;96(1):101-14.
• [28] Comparison of base-line and chemical-induced transcriptomic responses in HepaRG and RPTEC/TERT1 cells using TempO-Seq. Arch Toxicol. 2018 Aug;92(8):2517-2531.
• [29] Identification of differentially expressed genes in hepatic HepG2 cells treated with acetaminophen using suppression subtractive hybridization. Biol Pharm Bull. 2005 Jul;28(7):1148-53. doi: 10.1248/bpb.28.1148.
• [30] Auto-oxidation of Isoniazid Leads to Isonicotinic-Lysine Adducts on Human Serum Albumin. Chem Res Toxicol. 2015 Jan 20;28(1):51-8. doi: 10.1021/tx500285k. Epub 2014 Dec 9.
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• [32] The Isoniazid Metabolites Hydrazine and Pyridoxal Isonicotinoyl Hydrazone Modulate Heme Biosynthesis. Toxicol Sci. 2019 Mar 1;168(1):209-224. doi: 10.1093/toxsci/kfy294.
• [33] Quercetin protected against isoniazide-induced HepG2 cell apoptosis by activating the SIRT1/ERK pathway. J Biochem Mol Toxicol. 2019 Sep;33(9):e22369. doi: 10.1002/jbt.22369. Epub 2019 Jul 23.
• [34] AMPK activator acadesine fails to alleviate isoniazid-caused mitochondrial instability in HepG2 cells. J Appl Toxicol. 2017 Oct;37(10):1219-1224. doi: 10.1002/jat.3483. Epub 2017 May 29.
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• [36] Effects of N-acetyltransferase 2 (NAT2), CYP2E1 and Glutathione-S-transferase (GST) genotypes on the serum concentrations of isoniazid and metabolites in tuberculosis patients. J Toxicol Sci. 2008 May;33(2):187-95. doi: 10.2131/jts.33.187.
• [37] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966