General Information of Drug Combination (ID: DC654JN)

Drug Combination Name
Crizotinib Digitoxin
Indication
Disease Entry Status REF
High grade ovarian serous adenocarcinoma Investigative [1]
Component Drugs Crizotinib   DM4F29C Digitoxin   DMWVIGP
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL
High-throughput Screening Result Testing Cell Line: OVCAR-5
Zero Interaction Potency (ZIP) Score: 14.51
Bliss Independence Score: 21.38
Loewe Additivity Score: 10.44
LHighest Single Agent (HSA) Score: 20.99

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
Indication(s) of Crizotinib
Disease Entry ICD 11 Status REF
Non-small-cell lung cancer 2C25.Y Approved [2]
Crizotinib Interacts with 4 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Proto-oncogene c-Met (MET) TTNDSF4 MET_HUMAN Modulator [7]
ALK tyrosine kinase receptor (ALK) TTPMQSO ALK_HUMAN Modulator [7]
Proto-oncogene c-Ros (ROS1) TTSZ6Y3 ROS1_HUMAN Modulator [7]
HGF/Met signaling pathway (HGF/Met pathway) TTKA5LP NOUNIPROTAC Inhibitor [8]
------------------------------------------------------------------------------------
Crizotinib Interacts with 3 DTP Molecule(s)
DTP Name DTP ID UniProt ID Mode of Action REF
P-glycoprotein 1 (ABCB1) DTUGYRD MDR1_HUMAN Substrate [9]
Organic anion transporting polypeptide 1B1 (SLCO1B1) DT3D8F0 SO1B1_HUMAN Substrate [10]
Organic anion transporting polypeptide 1B3 (SLCO1B3) DT9C1TS SO1B3_HUMAN Substrate [10]
------------------------------------------------------------------------------------
Crizotinib Interacts with 2 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) DE4LYSA CP3A4_HUMAN Metabolism [11]
Cytochrome P450 3A5 (CYP3A5) DEIBDNY CP3A5_HUMAN Metabolism [11]
------------------------------------------------------------------------------------
Crizotinib Interacts with 45 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) OTQGYY83 CP3A4_HUMAN Increases Expression [12]
ATP-dependent translocase ABCB1 (ABCB1) OTEJROBO MDR1_HUMAN Decreases Activity [13]
Hepatocyte growth factor receptor (MET) OT7K55MU MET_HUMAN Increases Response To Substance [5]
ALK tyrosine kinase receptor (ALK) OTV3P4V8 ALK_HUMAN Decreases Response To Substance [14]
Prominin-1 (PROM1) OTBHV8NX PROM1_HUMAN Decreases Expression [4]
CD44 antigen (CD44) OT9TTJ41 CD44_HUMAN Decreases Expression [4]
Epithelial cell adhesion molecule (EPCAM) OTHBZK5X EPCAM_HUMAN Decreases Expression [4]
Cytidine deaminase (CDA) OT3HXP6N CDD_HUMAN Decreases Expression [4]
Insulin-induced gene 1 protein (INSIG1) OTZF5X1D INSI1_HUMAN Increases Expression [15]
Acyl-CoA 6-desaturase (FADS2) OTUX531P FADS2_HUMAN Increases Expression [15]
3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) OTRT3F3U HMDH_HUMAN Increases Expression [15]
Caspase-3 (CASP3) OTIJRBE7 CASP3_HUMAN Increases Activity [15]
Fatty acid synthase (FASN) OTFII9KG FAS_HUMAN Increases Expression [15]
Caspase-7 (CASP7) OTAPJ040 CASP7_HUMAN Increases Activity [15]
Hydroxymethylglutaryl-CoA synthase, cytoplasmic (HMGCS1) OTCO26FV HMCS1_HUMAN Increases Expression [15]
Sterol regulatory element-binding protein 2 (SREBF2) OTBXUNPL SRBP2_HUMAN Increases Expression [15]
Potassium voltage-gated channel subfamily H member 2 (KCNH2) OTZX881H KCNH2_HUMAN Decreases Activity [15]
Acetyl-CoA carboxylase 1 (ACACA) OT5CQPZY ACACA_HUMAN Increases Phosphorylation [15]
Voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C) OT6KFNMS CAC1C_HUMAN Decreases Activity [15]
Sodium channel protein type 5 subunit alpha (SCN5A) OTGYZWR6 SCN5A_HUMAN Decreases Activity [15]
Baculoviral IAP repeat-containing protein 5 (BIRC5) OTILXZYL BIRC5_HUMAN Decreases Expression [5]
Bcl-2-like protein 11 (BCL2L11) OTNQQWFJ B2L11_HUMAN Increases Expression [5]
Follitropin subunit beta (FSHB) OTGLS283 FSHB_HUMAN Decreases Secretion [16]
Lutropin subunit beta (LHB) OT5GBOVJ LSHB_HUMAN Decreases Secretion [16]
Tyrosine-protein kinase Lck (LCK) OT883FG9 LCK_HUMAN Decreases Activity [17]
Poly polymerase 1 (PARP1) OT310QSG PARP1_HUMAN Increases Cleavage [18]
Tissue factor (F3) OT3MSU3B TF_HUMAN Increases Expression [19]
Histone H2AX (H2AX) OT18UX57 H2AX_HUMAN Increases Phosphorylation [18]
Alanine aminotransferase 1 (GPT) OTOXOA0Q ALAT1_HUMAN Increases Secretion [20]
Mitogen-activated protein kinase 3 (MAPK3) OTCYKGKO MK03_HUMAN Decreases Phosphorylation [21]
Mitogen-activated protein kinase 1 (MAPK1) OTH85PI5 MK01_HUMAN Decreases Phosphorylation [21]
RAC-alpha serine/threonine-protein kinase (AKT1) OT8H2YY7 AKT1_HUMAN Decreases Phosphorylation [22]
Signal transducer and activator of transcription 3 (STAT3) OTAAGKYZ STAT3_HUMAN Decreases Phosphorylation [23]
Ras GTPase-activating-like protein IQGAP1 (IQGAP1) OTZRWTGA IQGA1_HUMAN Decreases Phosphorylation [24]
Small ribosomal subunit protein eS6 (RPS6) OTT4D1LN RS6_HUMAN Decreases Phosphorylation [23]
Baculoviral IAP repeat-containing protein 2 (BIRC2) OTFXFREP BIRC2_HUMAN Decreases Expression [5]
Caspase-8 (CASP8) OTA8TVI8 CASP8_HUMAN Increases Cleavage [25]
Echinoderm microtubule-associated protein-like 4 (EML4) OTJC45TA EMAL4_HUMAN Increases Mutagenesis [21]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2) OTW8V2V1 ABCG2_HUMAN Decreases Activity [13]
GTPase KRas (KRAS) OT78QCN8 RASK_HUMAN Decreases Response To Substance [26]
Pro-epidermal growth factor (EGF) OTANRJ0L EGF_HUMAN Decreases Response To Substance [22]
Epidermal growth factor receptor (EGFR) OTAPLO1S EGFR_HUMAN Decreases Response To Substance [26]
Mast/stem cell growth factor receptor Kit (KIT) OTHUY3VZ KIT_HUMAN Decreases Response To Substance [14]
Proheparin-binding EGF-like growth factor (HBEGF) OTLU00JS HBEGF_HUMAN Decreases Response To Substance [22]
Protransforming growth factor alpha (TGFA) OTPD1LL9 TGFA_HUMAN Decreases Response To Substance [22]
------------------------------------------------------------------------------------
⏷ Show the Full List of 45 DOT(s)
Indication(s) of Digitoxin
Disease Entry ICD 11 Status REF
Arrhythmia BC9Z Approved [3]
Congestive cardiac insufficiency BD1Z Approved [3]
Heart failure BD10-BD13 Approved [3]
Digitoxin Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Sodium/potassium-transporting ATPase (SPT ATPase) TTQ38E9 AT1A1_HUMAN; AT1A2_HUMAN; AT1A3_HUMAN; AT1B1_HUMAN; AT1B2_HUMAN; AT1B3_HUMAN Inhibitor [27]
------------------------------------------------------------------------------------
Digitoxin Interacts with 1 DTP Molecule(s)
DTP Name DTP ID UniProt ID Mode of Action REF
P-glycoprotein 1 (ABCB1) DTUGYRD MDR1_HUMAN Substrate [28]
------------------------------------------------------------------------------------
Digitoxin Interacts with 3 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) DE4LYSA CP3A4_HUMAN Metabolism [29]
UDP-glucuronosyltransferase 1A1 (UGT1A1) DEYGVN4 UD11_HUMAN Metabolism [30]
Sulfotransferase 1A1 (SULT1A1) DEYWLRK ST1A1_HUMAN Metabolism [31]
------------------------------------------------------------------------------------
Digitoxin Interacts with 22 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
ATP-dependent translocase ABCB1 (ABCB1) OTEJROBO MDR1_HUMAN Increases Transport [32]
Nitric oxide synthase 3 (NOS3) OTLDT7NR NOS3_HUMAN Increases Activity [33]
Serine/threonine-protein kinase Chk1 (CHEK1) OTTTI622 CHK1_HUMAN Decreases Expression [34]
Baculoviral IAP repeat-containing protein 5 (BIRC5) OTILXZYL BIRC5_HUMAN Decreases Expression [34]
Serine/threonine-protein kinase Chk2 (CHEK2) OT8ZPCNS CHK2_HUMAN Decreases Expression [34]
Cellular tumor antigen p53 (TP53) OTIE1VH3 P53_HUMAN Decreases Expression [34]
Cyclin-dependent kinase 1 (CDK1) OTW1SC2N CDK1_HUMAN Decreases Expression [34]
Interleukin-8 (CXCL8) OTS7T5VH IL8_HUMAN Decreases Secretion [35]
G2/mitotic-specific cyclin-B1 (CCNB1) OT19S7E5 CCNB1_HUMAN Decreases Expression [34]
Ribosomal protein S6 kinase beta-1 (RPS6KB1) OTAELNGX KS6B1_HUMAN Decreases Phosphorylation [36]
G1/S-specific cyclin-D1 (CCND1) OT8HPTKJ CCND1_HUMAN Decreases Expression [36]
NF-kappa-B inhibitor alpha (NFKBIA) OTFT924M IKBA_HUMAN Decreases Phosphorylation [35]
Tyrosine-protein phosphatase non-receptor type 6 (PTPN6) OT33XNZM PTN6_HUMAN Increases Expression [36]
Cyclin-dependent kinase inhibitor 1 (CDKN1A) OTQWHCZE CDN1A_HUMAN Decreases Expression [34]
Caspase-3 (CASP3) OTIJRBE7 CASP3_HUMAN Decreases Expression [34]
Cyclin-dependent kinase inhibitor 1B (CDKN1B) OTNY5LLZ CDN1B_HUMAN Decreases Expression [34]
Caspase-9 (CASP9) OTD4RFFG CASP9_HUMAN Increases Cleavage [34]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN) OTOWDUNT PTEN_HUMAN Increases Expression [36]
Cytochrome c (CYCS) OTBFALJD CYC_HUMAN Increases Expression [34]
Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1) OTHBQVD5 4EBP1_HUMAN Decreases Phosphorylation [36]
Caspase-8 (CASP8) OTA8TVI8 CASP8_HUMAN Increases Cleavage [34]
E3 SUMO-protein ligase PIAS3 (PIAS3) OT3TWH9R PIAS3_HUMAN Increases Expression [36]
------------------------------------------------------------------------------------
⏷ Show the Full List of 22 DOT(s)

Test Results of This Drug Combination in Other Disease Systems

Indication DrugCom ID Cell Line Status REF
Anaplastic large cell lymphoma DC2B108 SR Investigative [1]
Clear cell renal cell carcinoma DCBLO11 TK-10 Investigative [1]
Large cell lung carcinoma DC1V09B NCI-H460 Investigative [1]
Plasma cell myeloma DCYAASH RPMI-8226 Investigative [1]
------------------------------------------------------------------------------------

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: 4903).
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: 6782).
4 Enhancement of the antiproliferative activity of gemcitabine by modulation of c-Met pathway in pancreatic cancer. Curr Pharm Des. 2013;19(5):940-50.
5 Antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer positive for MET amplification. Mol Cancer Ther. 2012 Jul;11(7):1557-64. doi: 10.1158/1535-7163.MCT-11-0934. Epub 2012 Jun 22.
6 Aberrant expression of the transcriptional factor Twist1 promotes invasiveness in ALK-positive anaplastic large cell lymphoma. Cell Signal. 2012 Apr;24(4):852-8. doi: 10.1016/j.cellsig.2011.11.020. Epub 2011 Dec 8.
7 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
8 Met tyrosine kinase inhibitor, PF-2341066, suppresses growth and invasion of nasopharyngeal carcinoma.Drug Des Devel Ther. 2015 Aug 26;9:4897-907.
9 Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar. Int J Cancer. 2014 Mar 15;134(6):1484-94.
10 Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
11 Crizotinib for the treatment of non-small-cell lung cancer. Am J Health Syst Pharm. 2013 Jun 1;70(11):943-7.
12 Prediction of crizotinib-midazolam interaction using the Simcyp population-based simulator: comparison of CYP3A time-dependent inhibition between human liver microsomes versus hepatocytes. Drug Metab Dispos. 2013 Feb;41(2):343-52.
13 Editor's Highlight: PlacentalDisposition and Effects of Crizotinib: An Ex Vivo Study in the Isolated Dual-Side Perfused Human Cotyledon. Toxicol Sci. 2017 Jun 1;157(2):500-509. doi: 10.1093/toxsci/kfx063.
14 Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med. 2012 Feb 8;4(120):120ra17. doi: 10.1126/scitranslmed.3003316. Epub 2012 Jan 25.
15 Multi-parameter in vitro toxicity testing of crizotinib, sunitinib, erlotinib, and nilotinib in human cardiomyocytes. Toxicol Appl Pharmacol. 2013 Oct 1;272(1):245-55.
16 Rapid-onset hypogonadism secondary to crizotinib use in men with metastatic nonsmall cell lung cancer. Cancer. 2012 Nov 1;118(21):5302-9. doi: 10.1002/cncr.27450. Epub 2012 Apr 4.
17 Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem. 2011 Sep 22;54(18):6342-63. doi: 10.1021/jm2007613. Epub 2011 Aug 18.
18 ROS-dependent DNA damage contributes to crizotinib-induced hepatotoxicity via the apoptotic pathway. Toxicol Appl Pharmacol. 2019 Nov 15;383:114768. doi: 10.1016/j.taap.2019.114768. Epub 2019 Oct 19.
19 Elucidating mechanisms of toxicity using phenotypic data from primary human cell systems--a chemical biology approach for thrombosis-related side effects. Int J Mol Sci. 2015 Jan 5;16(1):1008-29. doi: 10.3390/ijms16011008.
20 Cytotoxicity of 34 FDA approved small-molecule kinase inhibitors in primary rat and human hepatocytes. Toxicol Lett. 2018 Jul;291:138-148. doi: 10.1016/j.toxlet.2018.04.010. Epub 2018 Apr 12.
21 Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Proc Natl Acad Sci U S A. 2011 May 3;108(18):7535-40. doi: 10.1073/pnas.1019559108. Epub 2011 Apr 18.
22 Paracrine receptor activation by microenvironment triggers bypass survival signals and ALK inhibitor resistance in EML4-ALK lung cancer cells. Clin Cancer Res. 2012 Jul 1;18(13):3592-602. doi: 10.1158/1078-0432.CCR-11-2972. Epub 2012 May 2.
23 Crizotinib-resistant mutants of EML4-ALK identified through an accelerated mutagenesis screen. Chem Biol Drug Des. 2011 Dec;78(6):999-1005. doi: 10.1111/j.1747-0285.2011.01239.x. Epub 2011 Oct 31.
24 Tyrosine phosphorylation of the scaffold protein IQGAP1 in the MET pathway alters function. J Biol Chem. 2020 Dec 25;295(52):18105-18121. doi: 10.1074/jbc.RA120.015891. Epub 2020 Oct 21.
25 Keratinocytes apoptosis contributes to crizotinib induced-erythroderma. Toxicol Lett. 2020 Feb 1;319:102-110. doi: 10.1016/j.toxlet.2019.11.007. Epub 2019 Nov 7.
26 Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res. 2012 Mar 1;18(5):1472-82. doi: 10.1158/1078-0432.CCR-11-2906. Epub 2012 Jan 10.
27 Treatment of congestive heart failure--current status of use of digitoxin. Eur J Clin Invest. 2001;31 Suppl 2:10-7.
28 The association of ABCB1 polymorphisms and elevated serum digitoxin concentrations in geriatric patients. Eur J Clin Pharmacol. 2008 Apr;64(4):367-72.
29 Species differences in the toxicity and cytochrome P450 IIIA-dependent metabolism of digitoxin. Mol Pharmacol. 1991 Nov;40(5):859-67.
30 Use of a human liver microsome bank in drug glucuronidation studies. Toxicol In Vitro. 1991;5(5-6):559-62.
31 Hydroxysteroid sulfotransferase and a specific UDP-glucuronosyltransferase are involved in the metabolism of digitoxin in man. Naunyn Schmiedebergs Arch Pharmacol. 1992 Aug;346(2):226-33.
32 Heterogeneous transport of digitalis-like compounds by P-glycoprotein in vesicular and cellular assays. Toxicol In Vitro. 2016 Apr;32:138-45. doi: 10.1016/j.tiv.2015.12.009. Epub 2015 Dec 17.
33 Digitoxin elicits anti-inflammatory and vasoprotective properties in endothelial cells: Therapeutic implications for the treatment of atherosclerosis? Atherosclerosis. 2009 Oct;206(2):390-6.
34 Digitoxin and a synthetic monosaccharide analog inhibit cell viability in lung cancer cells. Toxicol Appl Pharmacol. 2012 Jan 1;258(1):51-60. doi: 10.1016/j.taap.2011.10.007. Epub 2011 Oct 18.
35 Digitoxin mimics gene therapy with CFTR and suppresses hypersecretion of IL-8 from cystic fibrosis lung epithelial cells. Proc Natl Acad Sci U S A. 2004 May 18;101(20):7693-8. doi: 10.1073/pnas.0402030101. Epub 2004 May 10.
36 Digitoxin promotes apoptosis and inhibits proliferation and migration by reducing HIF-1 and STAT3 in KRAS mutant human colon cancer cells. Chem Biol Interact. 2022 Jan 5;351:109729. doi: 10.1016/j.cbi.2021.109729. Epub 2021 Oct 28.