Details of the Drug Combination

General Information of Drug Combination (ID: DCGLLP7)

• Drug Combination Name: Penicillamine + Idarubicin
• Indication: Glioblastoma?; Status: Investigative [1]
• Component Drugs:
  Penicillamine (DM40EF6): Small molecular drug
  Idarubicin (DMM0XGL): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: T98G
  Zero Interaction Potency (ZIP) Score: 21.24
  Bliss Independence Score: 21.24
  Loewe Additivity Score: 7.8
  LHighest Single Agent (HSA) Score: 7.8

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Penicillamine

Disease Entry	ICD 11	Status	REF
Cystinuria	5C60.2	Approved	[2]
Rheumatoid arthritis	FA20	Approved	[3]
Wilson disease	5C64.00	Investigative	[2]

Penicillamine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human immunodeficiency virus Tat protein (HIV tat)	TTT3ZC9	TAT_HV1H2	Inhibitor	[7]

Penicillamine Interacts with 47 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Elastin (ELN)	OTFSO7PG	ELN_HUMAN	Affects Localization	[8]
Collagen alpha-1(I) chain (COL1A1)	OTI31178	CO1A1_HUMAN	Increases ADR	[9]
Superoxide dismutase (SOD1)	OT39TA1L	SODC_HUMAN	Decreases Activity	[10]
Catalase (CAT)	OTHEBX9R	CATA_HUMAN	Decreases Expression	[11]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Decreases Expression	[11]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Increases Expression	[11]
Cytochrome P450 2E1 (CYP2E1)	OTHQ17JG	CP2E1_HUMAN	Increases Expression	[11]
Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1)	OTM0GDTP	IF2A_HUMAN	Increases Phosphorylation	[11]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[11]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[11]
Heat shock 70 kDa protein 1A (HSPA1A)	OTKGIE76	HS71A_HUMAN	Increases Expression	[11]
C-C motif chemokine 3 (CCL3)	OTW2H3ND	CCL3_HUMAN	Increases Expression	[11]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[11]
C-C motif chemokine 4 (CCL4)	OT6B8P25	CCL4_HUMAN	Increases Expression	[11]
Heat shock 70 kDa protein 6 (HSPA6)	OTH4S7WB	HSP76_HUMAN	Increases Expression	[11]
Early growth response protein 1 (EGR1)	OTCP6XGZ	EGR1_HUMAN	Increases Expression	[11]
Glutathione S-transferase Mu 3 (GSTM3)	OTLA2WJT	GSTM3_HUMAN	Increases Expression	[11]
Prostaglandin G/H synthase 1 (PTGS1)	OTHCRLEC	PGH1_HUMAN	Increases Expression	[11]
Growth arrest and DNA damage-inducible protein GADD45 alpha (GADD45A)	OTDRV63V	GA45A_HUMAN	Increases Expression	[11]
Heat shock 70 kDa protein 1-like (HSPA1L)	OTC2V1K6	HS71L_HUMAN	Increases Expression	[11]
Nitric oxide synthase, inducible (NOS2)	OTKKIOJ1	NOS2_HUMAN	Increases Expression	[11]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[11]
Flavin-containing monooxygenase 5 (FMO5)	OTTILF8T	FMO5_HUMAN	Increases Expression	[11]
Heat shock-related 70 kDa protein 2 (HSPA2)	OTSDET7B	HSP72_HUMAN	Increases Expression	[11]
Flavin-containing monooxygenase 1 (FMO1)	OTTHSQKP	FMO1_HUMAN	Increases Expression	[11]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[11]
Phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1)	OTXEE550	APR_HUMAN	Increases Expression	[11]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Decreases Expression	[11]
High affinity copper uptake protein 1 (SLC31A1)	OTXLRTUB	COPT1_HUMAN	Increases Expression	[12]
Haptoglobin (HP)	OTGUGAF9	HPT_HUMAN	Decreases Expression	[13]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Increases Expression	[14]
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Decreases Expression	[13]
Amyloid-beta precursor protein (APP)	OTKFD7R4	A4_HUMAN	Increases Metabolism	[15]
Myeloperoxidase (MPO)	OTOOXLIN	PERM_HUMAN	Decreases Secretion	[16]
Transcription factor Sp1 (SP1)	OTISPT4X	SP1_HUMAN	Increases Expression	[12]
Endoplasmic reticulum chaperone BiP (HSPA5)	OTFUIRAO	BIP_HUMAN	Increases Expression	[6]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[6]
Metallothionein-1X (MT1X)	OT9AKFVS	MT1X_HUMAN	Decreases Expression	[17]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Increases Expression	[18]
Lysyl oxidase homolog 2 (LOXL2)	OTRT46B5	LOXL2_HUMAN	Decreases Activity	[19]
HLA class I histocompatibility antigen, A alpha chain (HLA-A)	OTAH14LU	HLAA_HUMAN	Affects Response To Substance	[20]
MHC class I antigen (HLA-B)	OTGPIQEH	O19755_HUMAN	Increases ADR	[9]
HLA class I histocompatibility antigen, B alpha chain (HLA-B)	OTNXFWY2	HLAB_HUMAN	Affects Response To Substance	[21]
MHC class I antigen HLA-B18 (HLA-B18)	OTO1T7OA	O77967_HUMAN	Increases ADR	[9]
HLA-DR4 protein (HLA-DR4)	OTR8MHXB	O77963_HUMAN	Increases ADR	[9]
HLA class II histocompatibility antigen, DRB1 beta chain (HLA-DRB1)	OTRGGIFP	DRB1_HUMAN	Increases Response To Substance	[22]
HLA-DR3 (HLA-DRB1)	OTZ84GNP	Q29887_HUMAN	Increases ADR	[9]

Indication(s) of Idarubicin

Disease Entry	ICD 11	Status	REF
Acute myelogenous leukaemia	2A41	Approved	[4]
Acute myeloid leukaemia	2A60	Approved	[5]
Adult acute monocytic leukemia	N.A.	Approved	[4]
Childhood acute megakaryoblastic leukemia	N.A.	Approved	[4]
Leukemia	N.A.	Approved	[4]

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	[24]

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	[25]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[26]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[26]

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	[27]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[27]

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	[23]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[28]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Increases Activity	[23]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Increases Expression	[29]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Decreases Activity	[23]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[30]
Peroxisome proliferator-activated receptor delta (PPARD)	OTI4WTOP	PPARD_HUMAN	Decreases Activity	[23]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[31]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Decreases Activity	[23]

References

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• [2] Penicillamine 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: 7264).
• [4] Idarubicin FDA Label
• [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. (Ligand id: 7083).
• [6] N-acetyl cysteine and penicillamine induce apoptosis via the ER stress response-signaling pathway. Mol Carcinog. 2010 Jan;49(1):68-74. doi: 10.1002/mc.20578.
• [7] Docking studies reveal a selective binding of D-penicillamine to the transactivator protein of human immunodeficiency virus type 1. FEBS Lett. 2002 Apr 10;516(1-3):43-6.
• [8] Collagen and elastin changes in D-penicillamine-induced pseudoxanthoma elasticum-like skin. Br J Dermatol. 1986 Mar;114(3):381-8. doi: 10.1111/j.1365-2133.1986.tb02832.x.
• [9] 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.
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• [12] Mechanistic basis for overcoming platinum resistance using copper chelating agents. Mol Cancer Ther. 2012 Nov;11(11):2483-94. doi: 10.1158/1535-7163.MCT-12-0580. Epub 2012 Aug 21.
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• [14] Massive breast enlargement in a patient receiving D-penicillamine for systemic sclerosis. J Rheumatol. 1985 Oct;12(5):990-1.
• [15] Chelation and intercalation: complementary properties in a compound for the treatment of Alzheimer's disease. J Struct Biol. 2000 Jun;130(2-3):209-16. doi: 10.1006/jsbi.2000.4285.
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• [17] The effect of zinc and D-penicillamine in a stable human hepatoma ATP7B knockout cell line. PLoS One. 2014 Jun 3;9(6):e98809. doi: 10.1371/journal.pone.0098809. eCollection 2014.
• [18] Effect of common medications on the expression of SARS-CoV-2 entry receptors in liver tissue. Arch Toxicol. 2020 Dec;94(12):4037-4041. doi: 10.1007/s00204-020-02869-1. Epub 2020 Aug 17.
• [19] Abnormal deposition of collagen around hepatocytes in Wilson's disease is associated with hepatocyte specific expression of lysyl oxidase and lysyl oxidase like protein-2. J Hepatol. 2005 Sep;43(3):499-507. doi: 10.1016/j.jhep.2005.02.052.
• [20] Genetic markers in rheumatoid arthritis relationship to toxicity from D-penicillamine. J Rheumatol. 1986 Apr;13(2):269-73.
• [21] Longterm followup of treatment with D-penicillamine for rheumatoid arthritis: effectivity and toxicity in relation to HLA antigens. J Rheumatol. 1987 Dec;14(6):1115-9.
• [22] HLA-DR antigens and proteinuria induced by aurothioglucose and D-penicillamine in patients with rheumatoid arthritis. J Rheumatol. 1983 Dec;10(6):948-53.
• [23] 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.
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• [26] Amonafide L-malate is not a substrate for multidrug resistance proteins in secondary acute myeloid leukemia. Leukemia. 2008 Nov;22(11):2110-5.
• [27] In vitro evaluation of cytochrome P450-mediated drug interactions between cytarabine, idarubicin, itraconazole and caspofungin. Hematology. 2004 Jun;9(3):217-21.
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• [29] The use of biochemical markers in cardiotoxicity monitoring in patients treated for leukemia. Neoplasma. 2005;52(5):430-4.
• [30] 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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