Details of the Drug Combination

General Information of Drug Combination (ID: DC0SDYL)

• Drug Combination Name: Chlorothiazide + Idarubicin
• Indication: Glioblastoma?; Status: Investigative [1]
• Component Drugs:
  Chlorothiazide (DMLHESP): Small molecular drug
  Idarubicin (DMM0XGL): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: T98G
  Zero Interaction Potency (ZIP) Score: 8.66
  Bliss Independence Score: 8.66
  Loewe Additivity Score: 5.21
  LHighest Single Agent (HSA) Score: 5.21

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Chlorothiazide

Disease Entry	ICD 11	Status	REF
Chronic heart failure	BD1Z	Approved	[2]
Congestive heart failure	BD10	Approved	[3]
Edema	MG29	Approved	[2]

Chlorothiazide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Carbonic anhydrase II (CA-II)	TTANPDJ	CAH2_HUMAN	Inhibitor	[7]

Chlorothiazide Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[8]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[9]

Chlorothiazide Interacts with 70 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Volume-regulated anion channel subunit LRRC8B (LRRC8B)	OTH2LMJ4	LRC8B_HUMAN	Increases ADR	[10]
Growth arrest-specific protein 7 (GAS7)	OT0M5TNY	GAS7_HUMAN	Increases ADR	[10]
LisH domain-containing protein ARMC9 (ARMC9)	OT0MZER2	ARMC9_HUMAN	Increases ADR	[6]
E3 ubiquitin-protein ligase NEDD4-like (NEDD4L)	OT1B19RU	NED4L_HUMAN	Increases ADR	[11]
Protein-lysine 6-oxidase (LOX)	OT1C2HIU	LYOX_HUMAN	Increases ADR	[6]
Alpha-1,3-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase (MGAT1)	OT1E09PZ	MGAT1_HUMAN	Increases ADR	[6]
Adenylate cyclase type 9 (ADCY9)	OT1IZT5K	ADCY9_HUMAN	Increases ADR	[12]
Beta-arrestin-1 (ARRB1)	OT2NJS37	ARRB1_HUMAN	Increases ADR	[6]
Endoplasmic reticulum-Golgi intermediate compartment protein 1 (ERGIC1)	OT351FKB	ERGI1_HUMAN	Increases ADR	[10]
Neutral ceramidase (ASAH2)	OT47TIF3	ASAH2_HUMAN	Increases ADR	[6]
P2Y purinoceptor 2 (P2RY2)	OT47XN46	P2RY2_HUMAN	Increases ADR	[11]
Protein phosphatase 1 regulatory subunit 12A (PPP1R12A)	OT4AVU95	MYPT1_HUMAN	Increases ADR	[6]
Protein argonaute-2 (AGO2)	OT4JY32Q	AGO2_HUMAN	Increases ADR	[6]
Glutamate--cysteine ligase regulatory subunit (GCLM)	OT6CP234	GSH0_HUMAN	Increases ADR	[6]
Zinc transporter ZIP11 (SLC39A11)	OT71LCT2	S39AB_HUMAN	Increases ADR	[6]
Triple functional domain protein (TRIO)	OT71X1AK	TRIO_HUMAN	Increases ADR	[13]
Signaling threshold-regulating transmembrane adapter 1 (SIT1)	OT7MDF09	SIT1_HUMAN	Increases ADR	[10]
Cytosolic carboxypeptidase 4 (AGBL1)	OT8NQLH0	CBPC4_HUMAN	Increases ADR	[6]
2-oxoisovalerate dehydrogenase subunit beta, mitochondrial (BCKDHB)	OT8OSVYU	ODBB_HUMAN	Increases ADR	[6]
Apolipoprotein L3 (APOL3)	OT95SQHR	APOL3_HUMAN	Increases ADR	[10]
Proline-rich membrane anchor 1 (PRIMA1)	OT9ITT3P	PRIMA_HUMAN	Increases ADR	[11]
CD44 antigen (CD44)	OT9TTJ41	CD44_HUMAN	Increases ADR	[6]
Golgi integral membrane protein 4 (GOLIM4)	OTB5NV8A	GOLI4_HUMAN	Increases ADR	[6]
Protein Jade-1 (JADE1)	OTBPJIRI	JADE1_HUMAN	Increases ADR	[6]
Trinucleotide repeat-containing gene 6C protein (TNRC6C)	OTBR07PM	TNR6C_HUMAN	Increases ADR	[6]
NAD-capped RNA hydrolase NUDT12 (NUDT12)	OTBUY58C	NUD12_HUMAN	Increases ADR	[6]
Carbonic anhydrase-related protein 10 (CA10)	OTC3N1F6	CAH10_HUMAN	Increases ADR	[6]
Actin-like protein 7B (ACTL7B)	OTCG3IGE	ACL7B_HUMAN	Increases ADR	[13]
Growth/differentiation factor 3 (GDF3)	OTD3KGJK	GDF3_HUMAN	Increases ADR	[6]
Microtubule-associated tumor suppressor candidate 2 (MTUS2)	OTDBDH2L	MTUS2_HUMAN	Increases ADR	[11]
Coagulation factor V (F5)	OTDMZ3LT	FA5_HUMAN	Increases ADR	[14]
Storkhead-box protein 2 (STOX2)	OTE9BK02	STOX2_HUMAN	Increases ADR	[6]
Protein kinase C-binding protein NELL1 (NELL1)	OTF3TX3N	NELL1_HUMAN	Increases ADR	[6]
Disabled homolog 2-interacting protein (DAB2IP)	OTF456VC	DAB2P_HUMAN	Increases ADR	[6]
Dual specificity protein phosphatase CDC14C (CDC14C)	OTFJU7Y0	CC14C_HUMAN	Increases ADR	[6]
Unconventional myosin-X (MYO10)	OTHB78ZQ	MYO10_HUMAN	Increases ADR	[6]
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A)	OTHCDQ22	PRGC1_HUMAN	Increases ADR	[6]
Sodium- and chloride-dependent transporter XTRP3 (SLC6A20)	OTHRD4XO	S6A20_HUMAN	Increases ADR	[10]
FYVE, RhoGEF and PH domain-containing protein 6 (FGD6)	OTI0T62C	FGD6_HUMAN	Increases ADR	[10]
Insulin-like growth factor I (IGF1)	OTIIZR61	IGF1_HUMAN	Increases ADR	[6]
Cytochrome P450 7B1 (CYP7B1)	OTIKFYP6	CP7B1_HUMAN	Increases ADR	[6]
Pleckstrin homology-like domain family B member 1 (PHLDB1)	OTIRCB6I	PHLB1_HUMAN	Increases ADR	[6]
Muscarinic acetylcholine receptor M3 (CHRM3)	OTKSD095	ACM3_HUMAN	Increases ADR	[6]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases ADR	[15]
Natural killer cells antigen CD94 (KLRD1)	OTMYLOV4	KLRD1_HUMAN	Increases ADR	[6]
Retinoic acid receptor RXR-alpha (RXRA)	OTP1TBDM	RXRA_HUMAN	Increases ADR	[10]
Kazrin (KAZN)	OTPM7BYM	KAZRN_HUMAN	Increases ADR	[10]
Eyes absent homolog 2 (EYA2)	OTPVLA73	EYA2_HUMAN	Increases ADR	[6]
Piezo-type mechanosensitive ion channel component 2 (PIEZO2)	OTQ7AT38	PIEZ2_HUMAN	Increases ADR	[6]
PR domain zinc finger protein 1 (PRDM1)	OTQLSVBS	PRDM1_HUMAN	Increases ADR	[10]
Glutamate receptor ionotropic, NMDA 3A (GRIN3A)	OTQS9GYY	NMD3A_HUMAN	Increases ADR	[6]
Solute carrier family 35 member F1 (SLC35F1)	OTRXHR2P	S35F1_HUMAN	Increases ADR	[6]
Glutamate receptor ionotropic, NMDA 2A (GRIN2A)	OTTP0KN8	NMDE1_HUMAN	Increases ADR	[6]
Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1)	OTU0FC24	COX41_HUMAN	Increases ADR	[6]
Oligodendrocyte transcription factor 3 (OLIG3)	OTU8XLAF	OLIG3_HUMAN	Increases ADR	[6]
Protocadherin-15 (PCDH15)	OTU9C2EH	PCD15_HUMAN	Increases ADR	[6]
Erlin-1 (ERLIN1)	OTUOOODY	ERLN1_HUMAN	Increases ADR	[6]
Cancer/testis antigen 62 (CT62)	OTV9N4KM	CT62_HUMAN	Increases ADR	[6]
Matrilin-2 (MATN2)	OTVDR68G	MATN2_HUMAN	Increases ADR	[10]
PHD finger protein 10 (PHF10)	OTWDR4EX	PHF10_HUMAN	Increases ADR	[6]
Ras GTPase-activating-like protein IQGAP2 (IQGAP2)	OTX2UA7P	IQGA2_HUMAN	Increases ADR	[6]
NIPA-like protein 2 (NIPAL2)	OTX9UREP	NPAL2_HUMAN	Increases ADR	[6]
EF-hand calcium-binding domain-containing protein 11 (EFCAB11)	OTXDJ9R8	EFC11_HUMAN	Increases ADR	[6]
Juxtaposed with another zinc finger protein 1 (JAZF1)	OTXTYSYD	JAZF1_HUMAN	Increases ADR	[6]
Adhesion G-protein coupled receptor G6 (ADGRG6)	OTY2UBXO	AGRG6_HUMAN	Increases ADR	[6]
Branched-chain-amino-acid aminotransferase, cytosolic (BCAT1)	OTYHXLWZ	BCAT1_HUMAN	Increases ADR	[6]
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Increases ADR	[6]
Myocyte-specific enhancer factor 2C (MEF2C)	OTZGF1Y5	MEF2C_HUMAN	Increases ADR	[6]
Disintegrin and metalloproteinase domain-containing protein 12 (ADAM12)	OTZKOTDB	ADA12_HUMAN	Increases ADR	[6]
F-box only protein 8 (FBXO8)	OTZNGJGW	FBX8_HUMAN	Increases ADR	[6]

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	[17]

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	[18]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[19]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[19]

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	[20]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[20]

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	[16]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[21]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Increases Activity	[16]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Increases Expression	[22]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Decreases Activity	[16]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[23]
Peroxisome proliferator-activated receptor delta (PPARD)	OTI4WTOP	PPARD_HUMAN	Decreases Activity	[16]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[24]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Decreases Activity	[16]

References

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• [2] Chlorothiazide 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: 4835).
• [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] Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans. Pharmacogenomics J. 2014 Feb;14(1):35-40. doi: 10.1038/tpj.2013.3. Epub 2013 Feb 12.
• [7] Localization of diuretic effects along the loop of Henle: an in vivo microperfusion study in rats. Clin Sci (Lond). 2000 Apr;98(4):481-8.
• [8] ABCG2 modulates chlorothiazide permeability--in vitro-characterization of its interactions. Drug Metab Pharmacokinet. 2012;27(3):349-53.
• [9] Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics. Am J Physiol Renal Physiol. 2008 Apr;294(4):F867-73.
• [10] Genome-wide association study of chemotherapeutic agent-induced severe neutropenia/leucopenia for patients in Biobank Japan. Cancer Sci. 2013 Aug;104(8):1074-82. doi: 10.1111/cas.12186. Epub 2013 Jun 10.
• [11] A genome-wide association study of caffeine-related sleep disturbance: confirmation of a role for a common variant in the adenosine receptor. Sleep. 2012 Jul 1;35(7):967-75. doi: 10.5665/sleep.1962.
• [12] Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib. Circ Cardiovasc Genet. 2015 Apr;8(2):372-82. doi: 10.1161/CIRCGENETICS.114.000663. Epub 2015 Jan 11.
• [13] Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory neuropathy. J Med Genet. 2013 Sep;50(9):599-605. doi: 10.1136/jmedgenet-2012-101466. Epub 2013 Jun 17.
• [14] Factor V Leiden mutation and thromboembolism risk in women receiving adjuvant tamoxifen for breast cancer. J Natl Cancer Inst. 2010 Jul 7;102(13):942-9. doi: 10.1093/jnci/djq211. Epub 2010 Jun 16.
• [15] Coffee, CYP1A2 genotype, and risk of myocardial infarction. JAMA. 2006 Mar 8;295(10):1135-41. doi: 10.1001/jama.295.10.1135.
• [16] 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.
• [17] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [18] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [19] Amonafide L-malate is not a substrate for multidrug resistance proteins in secondary acute myeloid leukemia. Leukemia. 2008 Nov;22(11):2110-5.
• [20] In vitro evaluation of cytochrome P450-mediated drug interactions between cytarabine, idarubicin, itraconazole and caspofungin. Hematology. 2004 Jun;9(3):217-21.
• [21] 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.
• [22] The use of biochemical markers in cardiotoxicity monitoring in patients treated for leukemia. Neoplasma. 2005;52(5):430-4.
• [23] 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.
• [24] Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model. Toxicol Sci. 2013 Dec;136(2):581-94. doi: 10.1093/toxsci/kft205. Epub 2013 Sep 19.