Details of the Drug Combination

General Information of Drug Combination (ID: DCWYW12)

• Drug Combination Name: Lamivudine + Idarubicin
• Indication: Glioblastoma?; Status: Investigative [1]
• Component Drugs:
  Lamivudine (DMI347A): Small molecular drug
  Idarubicin (DMM0XGL): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: T98G
  Zero Interaction Potency (ZIP) Score: 17.54
  Bliss Independence Score: 17.54
  Loewe Additivity Score: 15.98
  LHighest Single Agent (HSA) Score: 15.98

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Lamivudine

Disease Entry	ICD 11	Status	REF
Chronic HBV infection	1E51.0Z	Approved	[2]
Chronic hepatitis B virus infection	N.A.	Approved	[3]
Human immunodeficiency virus infection	1C62	Approved	[2]
Human immunodeficiency virus-1 infection	1C62	Approved	[4]
Diarrhea	ME05.1	Investigative	[3]

Lamivudine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human immunodeficiency virus Reverse transcriptase (HIV RT)	TT84ETX	POL_HV1B1	Modulator	[7]

Lamivudine Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[8]
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[9]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[10]

Lamivudine Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Deoxy-5'-nucleotidase 1 (NT5C)	DE4E31Z	NT5C_HUMAN	Metabolism	[11]
Phosphorylcholine transferase A (PCYT1A)	DEQYXD4	PCY1A_HUMAN	Metabolism	[12]
Phosphorylethanolamine transferase (PCYT2)	DEIX1PO	PCY2_HUMAN	Metabolism	[12]

Lamivudine Interacts with 19 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Solute carrier family 22 member 2 (SLC22A2)	OTGFK1AL	S22A2_HUMAN	Increases Uptake	[13]
Solute carrier family 22 member 1 (SLC22A1)	OT7817I4	S22A1_HUMAN	Increases Uptake	[13]
BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like (BNIP3L)	OTJKOMXE	BNI3L_HUMAN	Increases Expression	[14]
G1/S-specific cyclin-E2 (CCNE2)	OTBBUKQQ	CCNE2_HUMAN	Decreases Expression	[15]
Metalloproteinase inhibitor 1 (TIMP1)	OTOXC51H	TIMP1_HUMAN	Decreases Expression	[16]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Expression	[16]
Interferon gamma (IFNG)	OTXG9JM7	IFNG_HUMAN	Increases Expression	[17]
Collagen alpha-1(III) chain (COL3A1)	OTT1EMLM	CO3A1_HUMAN	Decreases Expression	[18]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[19]
Interstitial collagenase (MMP1)	OTI4I2V1	MMP1_HUMAN	Increases Expression	[16]
Endothelin-1 (EDN1)	OTZCACEG	EDN1_HUMAN	Increases Secretion	[14]
Cyclin-A2 (CCNA2)	OTPHHYZJ	CCNA2_HUMAN	Decreases Expression	[15]
Nitric oxide synthase 3 (NOS3)	OTLDT7NR	NOS3_HUMAN	Decreases Phosphorylation	[14]
G1/S-specific cyclin-D2 (CCND2)	OTDULQF9	CCND2_HUMAN	Decreases Expression	[15]
Sodium-dependent serotonin transporter (SLC6A4)	OT6FGDLW	SC6A4_HUMAN	Increases Expression	[20]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[15]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Decreases Expression	[15]
Actin, aortic smooth muscle (ACTA2)	OTEDLG8E	ACTA_HUMAN	Decreases Expression	[18]
Solute carrier family 22 member 3 (SLC22A3)	OTQYGVXX	S22A3_HUMAN	Increases Uptake	[13]

Indication(s) of Idarubicin

Disease Entry	ICD 11	Status	REF
Acute myelogenous leukaemia	2A41	Approved	[5]
Acute myeloid leukaemia	2A60	Approved	[6]
Adult acute monocytic leukemia	N.A.	Approved	[5]
Childhood acute megakaryoblastic leukemia	N.A.	Approved	[5]
Leukemia	N.A.	Approved	[5]

Idarubicin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
DNA topoisomerase II (TOP2)	TT0IHXV	TOP2A_HUMAN; TOP2B_HUMAN	Modulator	[7]

Idarubicin Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 1 (ABCC1)	DTSYQGK	MRP1_HUMAN	Substrate	[22]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[23]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[23]

Idarubicin Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[24]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[24]

Idarubicin Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Estrogen receptor (ESR1)	OTKLU61J	ESR1_HUMAN	Decreases Activity	[21]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[25]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Increases Activity	[21]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Increases Expression	[26]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Decreases Activity	[21]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[27]
Peroxisome proliferator-activated receptor delta (PPARD)	OTI4WTOP	PPARD_HUMAN	Decreases Activity	[21]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[28]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Decreases Activity	[21]

References

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• [2] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [3] Lamivudine FDA Label
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] Idarubicin FDA Label
• [6] 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: 7083).
• [7] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
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• [14] Nucleoside reverse transcriptase inhibitors induce a mitophagy-associated endothelial cytotoxicity that is reversed by coenzyme Q10 cotreatment. Toxicol Sci. 2013 Aug;134(2):323-34. doi: 10.1093/toxsci/kft105. Epub 2013 May 2.
• [15] Zidovudine induces S-phase arrest and cell cycle gene expression changes in human cells. Mutagenesis. 2005 Mar;20(2):139-46. doi: 10.1093/mutage/gei019. Epub 2005 Mar 22.
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• [17] Lamivudine plus interleukin-12 combination therapy in chronic hepatitis B: antiviral and immunological activity. Hepatology. 2005 Nov;42(5):1028-36. doi: 10.1002/hep.20888.
• [18] Decreasing fibrogenesis: an immunohistochemical study of paired liver biopsies following lamivudine therapy for chronic hepatitis B. J Hepatol. 2001 Dec;35(6):749-55. doi: 10.1016/s0168-8278(01)00218-5.
• [19] Binding of anti-HIV drugs to human serum albumin. IUBMB Life. 2004 Oct;56(10):609-14. doi: 10.1080/15216540400016286.
• [20] Serotonin transporter mRNA expression is decreased by lamivudine and ribavirin and increased by interferon in immune cells. Scand J Immunol. 2006 Feb;63(2):106-15. doi: 10.1111/j.1365-3083.2005.01715.x.
• [21] Quantitative high-throughput profiling of environmental chemicals and drugs that modulate farnesoid X receptor. Sci Rep. 2014 Sep 26;4:6437. doi: 10.1038/srep06437.
• [22] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [23] Amonafide L-malate is not a substrate for multidrug resistance proteins in secondary acute myeloid leukemia. Leukemia. 2008 Nov;22(11):2110-5.
• [24] In vitro evaluation of cytochrome P450-mediated drug interactions between cytarabine, idarubicin, itraconazole and caspofungin. Hematology. 2004 Jun;9(3):217-21.
• [25] A Quantitative Approach to Screen for Nephrotoxic Compounds In Vitro. J Am Soc Nephrol. 2016 Apr;27(4):1015-28. doi: 10.1681/ASN.2015010060. Epub 2015 Aug 10.
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• [27] The induction of apoptosis by daunorubicin and idarubicin in human trisomic and diabetic fibroblasts. Cell Mol Biol Lett. 2008;13(2):182-94. doi: 10.2478/s11658-007-0045-7. Epub 2008 Apr 10.
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