Details of the Drug Combination

General Information of Drug Combination (ID: DCE88B8)

• Drug Combination Name: Wortmannin + Idarubicin
• Indication: Glioblastoma?; Status: Investigative [1]
• Component Drugs:
  Wortmannin (DM8EVK5): Small molecular drug
  Idarubicin (DMM0XGL): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: T98G
  Zero Interaction Potency (ZIP) Score: 18.71
  Bliss Independence Score: 18.71
  Loewe Additivity Score: 28.85
  LHighest Single Agent (HSA) Score: 28.89

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Wortmannin

Disease Entry	ICD 11	Status	REF
Haematological malignancy	2B33.Y	Terminated	[2]

Wortmannin Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
PI3-kinase delta (PIK3CD)	TTGBPJE	PK3CD_HUMAN	Inhibitor	[6]
PI3-kinase gamma (PIK3CG)	TTHBTOP	PK3CG_HUMAN	Inhibitor	[7]

Wortmannin Interacts with 40 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
G1/S-specific cyclin-D2 (CCND2)	OTDULQF9	CCND2_HUMAN	Increases Expression	[8]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[9]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Decreases Expression	[10]
Serine/threonine-protein kinase Chk1 (CHEK1)	OTTTI622	CHK1_HUMAN	Decreases Expression	[11]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[12]
Forkhead box protein O3 (FOXO3)	OTHXQG4P	FOXO3_HUMAN	Decreases Phosphorylation	[5]
Serine/threonine-protein kinase Chk2 (CHEK2)	OT8ZPCNS	CHK2_HUMAN	Decreases Phosphorylation	[13]
Insulin-like growth factor II (IGF2)	OTJ4O6MW	IGF2_HUMAN	Decreases Response To Substance	[14]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases Response To Substance	[15]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Decreases Phosphorylation	[13]
72 kDa type IV collagenase (MMP2)	OT5NIWA2	MMP2_HUMAN	Decreases Expression	[16]
Intestinal-type alkaline phosphatase (ALPI)	OTTQ468O	PPBI_HUMAN	Increases Activity	[17]
Heat shock 70 kDa protein 1A (HSPA1A)	OTKGIE76	HS71A_HUMAN	Decreases Expression	[18]
Cadherin-1 (CDH1)	OTFJMXPM	CADH1_HUMAN	Increases Expression	[5]
Secretogranin-2 (SCG2)	OTUHXX8U	SCG2_HUMAN	Decreases Activity	[19]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Decreases Activity	[20]
Ribosomal protein S6 kinase beta-1 (RPS6KB1)	OTAELNGX	KS6B1_HUMAN	Decreases Phosphorylation	[21]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Affects Response To Substance	[15]
Metallothionein-3 (MT3)	OTVCZ7HI	MT3_HUMAN	Decreases Response To Substance	[22]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[23]
Phosphatidylinositol 3-kinase regulatory subunit alpha (PIK3R1)	OT5BZ1J9	P85A_HUMAN	Decreases Activity	[24]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[23]
Nitric oxide synthase 3 (NOS3)	OTLDT7NR	NOS3_HUMAN	Decreases Phosphorylation	[25]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Activity	[26]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Decreases Expression	[27]
Glucose-6-phosphatase catalytic subunit 1 (G6PC1)	OTJ6FM9F	G6PC1_HUMAN	Increases Expression	[28]
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA)	OTTOMI8J	PK3CA_HUMAN	Decreases Activity	[24]
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform (PIK3CB)	OTO8JQJA	PK3CB_HUMAN	Decreases Activity	[29]
Glycogen synthase kinase-3 beta (GSK3B)	OTL3L14B	GSK3B_HUMAN	Decreases Phosphorylation	[18]
Selenoprotein P (SELENOP)	OT02B8IR	SEPP1_HUMAN	Increases Expression	[28]
Heat shock factor protein 1 (HSF1)	OTYNJ4KP	HSF1_HUMAN	Affects Localization	[18]
Myosin regulatory light chain 2, atrial isoform (MYL7)	OT7ZNDP4	MLRA_HUMAN	Decreases Phosphorylation	[30]
Elongation factor 1-alpha 2 (EEF1A2)	OT9Z23K5	EF1A2_HUMAN	Increases Expression	[31]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[32]
Baculoviral IAP repeat-containing protein 2 (BIRC2)	OTFXFREP	BIRC2_HUMAN	Decreases Expression	[12]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Decreases Expression	[33]
Programmed cell death protein 4 (PDCD4)	OTZ6NXUX	PDCD4_HUMAN	Increases Expression	[34]
Krueppel-like factor 6 (KLF6)	OTQY9S7F	KLF6_HUMAN	Decreases Expression	[35]
Growth/differentiation factor 15 (GDF15)	OTWQN50N	GDF15_HUMAN	Increases Expression	[36]
Forkhead box protein P1 (FOXP1)	OTSG6XGF	FOXP1_HUMAN	Decreases Expression	[21]

Indication(s) of Idarubicin

Disease Entry	ICD 11	Status	REF
Acute myelogenous leukaemia	2A41	Approved	[3]
Acute myeloid leukaemia	2A60	Approved	[4]
Adult acute monocytic leukemia	N.A.	Approved	[3]
Childhood acute megakaryoblastic leukemia	N.A.	Approved	[3]
Leukemia	N.A.	Approved	[3]

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	[38]

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	[39]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[40]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[40]

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	[41]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[41]

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	[37]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[42]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Increases Activity	[37]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Increases Expression	[43]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Decreases Activity	[37]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[44]
Peroxisome proliferator-activated receptor delta (PPARD)	OTI4WTOP	PPARD_HUMAN	Decreases Activity	[37]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[45]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Decreases Activity	[37]

References

• [1] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [2] 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: 6060).
• [3] Idarubicin FDA Label
• [4] 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).
• [5] (-)-Liriopein B Suppresses Breast Cancer Progression via Inhibition of Multiple Kinases. Chem Res Toxicol. 2015 May 18;28(5):897-906. doi: 10.1021/tx500518j. Epub 2015 Apr 21.
• [6] Selective role of PI3K delta in neutrophil inflammatory responses. Biochem Biophys Res Commun. 2003 Sep 5;308(4):764-9.
• [7] Phosphatidylinositol 3-kinase/Akt signaling in the response of vascular endothelium to ionizing radiation. Cancer Res. 2002 Aug 15;62(16):4671-7.
• [8] Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal. Mol Psychiatry. 2004 Apr;9(4):358-70.
• [9] Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol Sci. 2010 Dec; 118(2):485-500.
• [10] The dietary phytochemical 3,3'-diindolylmethane induces G2/M arrest and apoptosis in oral squamous cell carcinoma by modulating Akt-NF-B, MAPK, and p53 signaling. Chem Biol Interact. 2012 Feb 5;195(3):224-30.
• [11] H2AX, pChk1, and Wip1 as potential markers of persistent DNA damage derived from dibenzo[a,l]pyrene and PAH-containing extracts from contaminated soils. Chem Res Toxicol. 2012 Apr 16;25(4):862-72. doi: 10.1021/tx200436n. Epub 2012 Mar 22.
• [12] Phosphatidylinositol 3-kinase inhibition down-regulates survivin and facilitates TRAIL-mediated apoptosis in neuroblastomas. J Pediatr Surg. 2004 Apr;39(4):516-21. doi: 10.1016/j.jpedsurg.2003.12.008.
• [13] DNA damage responses in cells exposed to sulphur mustard. Toxicol Lett. 2012 Feb 25;209(1):1-10. doi: 10.1016/j.toxlet.2011.11.009. Epub 2011 Nov 18.
• [14] Induction of steroid sulfatase expression in PC-3 human prostate cancer cells by insulin-like growth factor II. Toxicol Lett. 2013 Nov 25;223(2):109-15. doi: 10.1016/j.toxlet.2013.09.006. Epub 2013 Sep 18.
• [15] PI3K/AKT inhibitors aggravate death receptor-mediated hepatocyte apoptosis and liver injury. Toxicol Appl Pharmacol. 2019 Oct 15;381:114729. doi: 10.1016/j.taap.2019.114729. Epub 2019 Aug 22.
• [16] Brazilein suppresses migration and invasion of MDA-MB-231 breast cancer cells. Chem Biol Interact. 2013 Jul 5;204(2):105-15. doi: 10.1016/j.cbi.2013.05.005. Epub 2013 May 21.
• [17] Methotrexate induced differentiation in colon cancer cells is primarily due to purine deprivation. J Cell Biochem. 2006 Sep 1;99(1):146-55. doi: 10.1002/jcb.20908.
• [18] Modulation of Akt and ERK1/2 pathways by resveratrol in chronic myelogenous leukemia (CML) cells results in the downregulation of Hsp70. PLoS One. 2010 Jan 14;5(1):e8719. doi: 10.1371/journal.pone.0008719.
• [19] Secretoneurin, a novel neuropeptide, is a potent chemoattractant for human eosinophils. Blood. 1998 Mar 1;91(5):1527-32.
• [20] Antimetastatic effect and mechanism of ovatodiolide in MDA-MB-231 human breast cancer cells. Chem Biol Interact. 2011 Nov 15;194(2-3):148-58. doi: 10.1016/j.cbi.2011.10.002. Epub 2011 Oct 19.
• [21] FOXP1 regulation via the PI3K/Akt/p70S6K signaling pathway in breast cancer cells. Oncol Lett. 2015 Mar;9(3):1482-1488. doi: 10.3892/ol.2015.2885. Epub 2015 Jan 16.
• [22] Metallothionein-III provides neuronal protection through activation of nuclear factor-kappaB via the TrkA/phosphatidylinositol-3 kinase/Akt signaling pathway. Toxicol Sci. 2009 Dec;112(2):435-49. doi: 10.1093/toxsci/kfp230. Epub 2009 Sep 18.
• [23] Preclinical pharmacological evaluation of a novel multiple kinase inhibitor, ON123300, in brain tumor models. Mol Cancer Ther. 2014 May;13(5):1105-16. doi: 10.1158/1535-7163.MCT-13-0847. Epub 2014 Feb 25.
• [24] Expression and purification of PI3 kinase alpha and development of an ATP depletion and an alphascreen PI3 kinase activity assay. J Biomol Screen. 2008 Dec;13(10):1035-40. doi: 10.1177/1087057108326079. Epub 2008 Nov 25.
• [25] Fenofibrate activates AMPK and increases eNOS phosphorylation in HUVEC. Biochem Biophys Res Commun. 2006 Mar 24;341(4):973-8. doi: 10.1016/j.bbrc.2006.01.052. Epub 2006 Jan 24.
• [26] The phosphoinositide 3-kinase/AKT1 pathway involvement in drug and all-trans-retinoic acid resistance of leukemia cells. Mol Cancer Res. 2003 Jan;1(3):234-46.
• [27] Regulation and possible function of beta-catenin in human monocytes. J Immunol. 2001 Dec 15;167(12):6786-93. doi: 10.4049/jimmunol.167.12.6786.
• [28] Acute and long-term effects of arsenite in HepG2 cells: modulation of insulin signaling. Biometals. 2014 Apr;27(2):317-32. doi: 10.1007/s10534-014-9714-y. Epub 2014 Feb 18.
• [29] Effect of semi-synthesized quercetin water-soluble derivatives on recombinant human phosphatidylinositol 3-kinase p110beta catalytic subunit. Acta Pharmacol Sin. 2002 Apr;23(4):339-42.
• [30] Key role of myosin light chain (MLC) kinase-mediated MLC2a phosphorylation in the alpha 1-adrenergic positive inotropic effect in human atrium. Cardiovasc Res. 2005 Jan 1;65(1):211-20. doi: 10.1016/j.cardiores.2004.09.019.
• [31] eEF1A2 siRNA Suppresses MPP(+)-Induced Activation of Akt and mTOR and Potentiates Caspase-3 Activation in a Parkinson's Disease Model. ScientificWorldJournal. 2023 Apr 3;2023:1335201. doi: 10.1155/2023/1335201. eCollection 2023.
• [32] ABT-737 resistance in B-cells isolated from chronic lymphocytic leukemia patients and leukemia cell lines is overcome by the pleiotropic kinase inhibitor quercetin through Mcl-1 down-regulation. Biochem Pharmacol. 2013 Apr 1;85(7):927-36. doi: 10.1016/j.bcp.2013.01.011. Epub 2013 Jan 24.
• [33] PI3K/Akt is required for heat shock proteins to protect hypoxia-inducible factor 1alpha from pVHL-independent degradation. J Biol Chem. 2004 Apr 2;279(14):13506-13. doi: 10.1074/jbc.M310164200. Epub 2004 Jan 15.
• [34] Programmed cell death-4 tumor suppressor protein contributes to retinoic acid-induced terminal granulocytic differentiation of human myeloid leukemia cells. Mol Cancer Res. 2007 Jan;5(1):95-108. doi: 10.1158/1541-7786.MCR-06-0125.
• [35] Oxidative stress modulates KLF6Full and its splice variants. Alcohol Clin Exp Res. 2012 Nov;36(11):1851-62. doi: 10.1111/j.1530-0277.2012.01798.x. Epub 2012 Apr 6.
• [36] Aspidin PB, a phloroglucinol derivative, induces apoptosis in human hepatocarcinoma HepG2 cells by modulating PI3K/Akt/GSK3 pathway. Chem Biol Interact. 2013 Jan 25;201(1-3):1-8. doi: 10.1016/j.cbi.2012.11.005. Epub 2012 Nov 21.
• [37] 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.
• [38] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [39] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [40] Amonafide L-malate is not a substrate for multidrug resistance proteins in secondary acute myeloid leukemia. Leukemia. 2008 Nov;22(11):2110-5.
• [41] In vitro evaluation of cytochrome P450-mediated drug interactions between cytarabine, idarubicin, itraconazole and caspofungin. Hematology. 2004 Jun;9(3):217-21.
• [42] 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.
• [43] The use of biochemical markers in cardiotoxicity monitoring in patients treated for leukemia. Neoplasma. 2005;52(5):430-4.
• [44] 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.
• [45] 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.