General Information of Drug Combination (ID: DC24IBD)

Drug Combination Name
FORMONONETIN Romidepsin
Indication
Disease Entry Status REF
Ewing sarcoma Investigative [1]
Component Drugs FORMONONETIN   DM7WFZ8 Romidepsin   DMT5GNL
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL
High-throughput Screening Result Testing Cell Line: TC-71
Zero Interaction Potency (ZIP) Score: 7.241
Bliss Independence Score: 5.877
Loewe Additivity Score: 2.972
LHighest Single Agent (HSA) Score: 5.749

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
Indication(s) of FORMONONETIN
Disease Entry ICD 11 Status REF
Discovery agent N.A. Investigative [2]
FORMONONETIN Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
SLC5A2 messenger RNA (SLC5A2 mRNA) TTF8JAT SC5A2_HUMAN Inhibitor [2]
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FORMONONETIN Interacts with 19 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Cytochrome P450 1A2 (CYP1A2) OTLLBX48 CP1A2_HUMAN Decreases Activity [7]
Cytochrome P450 2D6 (CYP2D6) OTZJC802 CP2D6_HUMAN Decreases Activity [7]
Cytochrome P450 1A1 (CYP1A1) OTE4EFH8 CP1A1_HUMAN Increases Expression [8]
Aryl hydrocarbon receptor (AHR) OTFE4EYE AHR_HUMAN Increases Activity [8]
Cytochrome P450 1B1 (CYP1B1) OTYXFLSD CP1B1_HUMAN Increases Expression [8]
Erythropoietin (EPO) OTZ90CN4 EPO_HUMAN Increases Expression [9]
Estrogen receptor (ESR1) OTKLU61J ESR1_HUMAN Affects Binding [10]
Cellular tumor antigen p53 (TP53) OTIE1VH3 P53_HUMAN Decreases Expression [11]
ATP-dependent translocase ABCB1 (ABCB1) OTEJROBO MDR1_HUMAN Increases Expression [12]
Apoptosis regulator Bcl-2 (BCL2) OT9DVHC0 BCL2_HUMAN Decreases Expression [12]
G2/mitotic-specific cyclin-B1 (CCNB1) OT19S7E5 CCNB1_HUMAN Increases Expression [11]
G1/S-specific cyclin-D1 (CCND1) OT8HPTKJ CCND1_HUMAN Increases Expression [11]
Multidrug resistance-associated protein 1 (ABCC1) OTGUN89S MRP1_HUMAN Decreases Expression [12]
Caspase-3 (CASP3) OTIJRBE7 CASP3_HUMAN Increases Expression [12]
Caspase-9 (CASP9) OTD4RFFG CASP9_HUMAN Increases Expression [12]
Caspase-8 (CASP8) OTA8TVI8 CASP8_HUMAN Increases Expression [12]
Hypoxia-inducible factor 1-alpha (HIF1A) OTADSC03 HIF1A_HUMAN Increases Expression [9]
Estrogen receptor beta (ESR2) OTXNR2WQ ESR2_HUMAN Affects Binding [13]
ATP-binding cassette sub-family C member 2 (ABCC2) OTJSIGV5 MRP2_HUMAN Decreases Expression [12]
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⏷ Show the Full List of 19 DOT(s)
Indication(s) of Romidepsin
Disease Entry ICD 11 Status REF
Cutaneous T-cell lymphoma 2B01 Approved [3]
Gastrin-producing neuroendocrine tumor N.A. Approved [4]
Glucagonoma N.A. Approved [4]
Insulinoma 2C10.1 Approved [4]
Lung carcinoid tumor N.A. Approved [4]
Melanoma 2C30 Approved [4]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified N.A. Approved [4]
Primary cutaneous T-cell lymphoma N.A. Approved [4]
Urethral cancer 2C93 Approved [4]
Peripheral T-cell lymphoma 2A90.C Phase 3 [5]
Renal cell carcinoma 2C90 Phase 3 [3]
Romidepsin Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Histone deacetylase 1 (HDAC1) TT6R7JZ HDAC1_HUMAN Inhibitor [16]
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Romidepsin Interacts with 2 DTP Molecule(s)
DTP Name DTP ID UniProt ID Mode of Action REF
P-glycoprotein 1 (ABCB1) DTUGYRD MDR1_HUMAN Substrate [17]
Organic anion transporting polypeptide 1B3 (SLCO1B3) DT9C1TS SO1B3_HUMAN Substrate [17]
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Romidepsin Interacts with 3 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) DE4LYSA CP3A4_HUMAN Metabolism [18]
Cytochrome P450 3A5 (CYP3A5) DEIBDNY CP3A5_HUMAN Metabolism [19]
Cytochrome P450 2B6 (CYP2B6) DEPKLMQ CP2B6_HUMAN Metabolism [20]
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Romidepsin Interacts with 41 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
ATP-dependent translocase ABCB1 (ABCB1) OTEJROBO MDR1_HUMAN Increases Expression [21]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2) OTW8V2V1 ABCG2_HUMAN Affects Expression [22]
E3 SUMO-protein ligase CBX4 (CBX4) OT4XVRRF CBX4_HUMAN Increases Expression [23]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B) OTA1CPBV TR10B_HUMAN Increases Expression [24]
Bcl-2-like protein 11 (BCL2L11) OTNQQWFJ B2L11_HUMAN Increases Expression [25]
Growth arrest and DNA damage-inducible protein GADD45 beta (GADD45B) OTL9I7LO GA45B_HUMAN Increases Expression [26]
Serine/threonine-protein kinase 17B (STK17B) OT4NYNO8 ST17B_HUMAN Increases Expression [23]
Epidermal growth factor receptor (EGFR) OTAPLO1S EGFR_HUMAN Decreases Expression [27]
RAF proto-oncogene serine/threonine-protein kinase (RAF1) OT51LSFO RAF1_HUMAN Decreases Expression [27]
Receptor tyrosine-protein kinase erbB-2 (ERBB2) OTOAUNCK ERBB2_HUMAN Decreases Expression [27]
Retinoblastoma-associated protein (RB1) OTQJUJMZ RB_HUMAN Decreases Phosphorylation [27]
Poly polymerase 1 (PARP1) OT310QSG PARP1_HUMAN Increases Cleavage [28]
Clusterin (CLU) OTQGG0JM CLUS_HUMAN Increases Expression [23]
G2/mitotic-specific cyclin-B1 (CCNB1) OT19S7E5 CCNB1_HUMAN Decreases Expression [27]
Histone H2AX (H2AX) OT18UX57 H2AX_HUMAN Increases Phosphorylation [15]
Transcription factor JunD (JUND) OTNKACJD JUND_HUMAN Increases Expression [23]
Nuclear factor NF-kappa-B p105 subunit (NFKB1) OTNRRD8I NFKB1_HUMAN Increases Expression [28]
Cyclin-A2 (CCNA2) OTPHHYZJ CCNA2_HUMAN Decreases Expression [27]
NF-kappa-B inhibitor alpha (NFKBIA) OTFT924M IKBA_HUMAN Increases Expression [28]
Mitogen-activated protein kinase 3 (MAPK3) OTCYKGKO MK03_HUMAN Decreases Phosphorylation [15]
Mitogen-activated protein kinase 1 (MAPK1) OTH85PI5 MK01_HUMAN Decreases Phosphorylation [15]
RAC-alpha serine/threonine-protein kinase (AKT1) OT8H2YY7 AKT1_HUMAN Increases Phosphorylation [29]
Receptor-type tyrosine-protein kinase FLT3 (FLT3) OTMSRYMK FLT3_HUMAN Decreases Phosphorylation [15]
Sterol regulatory element-binding protein 1 (SREBF1) OTWBRPAI SRBP1_HUMAN Increases Expression [23]
Cyclin-dependent kinase inhibitor 1 (CDKN1A) OTQWHCZE CDN1A_HUMAN Increases Expression [30]
Caspase-3 (CASP3) OTIJRBE7 CASP3_HUMAN Increases Activity [27]
Caspase-9 (CASP9) OTD4RFFG CASP9_HUMAN Increases Cleavage [28]
Friend leukemia integration 1 transcription factor (FLI1) OT0EV3LX FLI1_HUMAN Decreases Expression [31]
RNA-binding protein EWS (EWSR1) OT7SRHV3 EWS_HUMAN Decreases Expression [31]
DNA repair protein RAD51 homolog 1 (RAD51) OTNVWGC1 RAD51_HUMAN Decreases Expression [15]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) OT2YYI1A MCL1_HUMAN Increases Expression [29]
Bcl-2-interacting killer (BIK) OTTH1T3D BIK_HUMAN Increases Expression [23]
Spectrin alpha chain, non-erythrocytic 1 (SPTAN1) OT6VY3A3 SPTN1_HUMAN Increases Expression [23]
Nuclear receptor subfamily 1 group I member 3 (NR1I3) OTS3SGH7 NR1I3_HUMAN Increases Expression [32]
Bcl-2 homologous antagonist/killer (BAK1) OTDP6ILW BAK_HUMAN Increases Expression [29]
Histone H3.1t (H3-4) OTY6ITYF H31T_HUMAN Increases Acetylation [32]
Sodium/iodide cotransporter (SLC5A5) OTU7E9G7 SC5A5_HUMAN Increases Expression [33]
Mitogen-activated protein kinase kinase kinase 3 (MAP3K3) OT53LJGW M3K3_HUMAN Increases Expression [23]
Cytochrome P450 1A1 (CYP1A1) OTE4EFH8 CP1A1_HUMAN Affects Metabolism [34]
Multidrug resistance-associated protein 1 (ABCC1) OTGUN89S MRP1_HUMAN Decreases Response To Substance [35]
Transcription factor p65 (RELA) OTUJP9CN TF65_HUMAN Decreases Response To Substance [28]
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⏷ Show the Full List of 41 DOT(s)

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 Na+-glucose cotransporter (SGLT) inhibitory flavonoids from the roots of Sophora flavescens. Bioorg Med Chem. 2007 May 15;15(10):3445-9.
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: 7006).
4 Romidepsin FDA Label
5 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
6 Differential and special properties of the major human UGT1-encoded gastrointestinal UDP-glucuronosyltransferases enhance potential to control chemical uptake. J Biol Chem. 2004 Jan 9;279(2):1429-41.
7 In vivo prediction of CYP-mediated metabolic interaction potential of formononetin and biochanin A using in vitro human and rat CYP450 inhibition data. Toxicol Lett. 2015 Nov 19;239(1):1-8.
8 Red clover aryl hydrocarbon receptor (AhR) and estrogen receptor (ER) agonists enhance genotoxic estrogen metabolism. Chem Res Toxicol. 2017 Nov 20;30(11):2084-2092.
9 Flavonoids from Radix Astragali induce the expression of erythropoietin in cultured cells: a signaling mediated via the accumulation of hypoxia-inducible factor-1. J Agric Food Chem. 2011 Mar 9;59(5):1697-704. doi: 10.1021/jf104018u. Epub 2011 Feb 10.
10 Estrogenic activity of isoflavonoids from Onobrychis ebenoides. Planta Med. 2006 May;72(6):488-93. doi: 10.1055/s-2005-916261.
11 Targeting Oct2 and P53: Formononetin prevents cisplatin-induced acute kidney injury. Toxicol Appl Pharmacol. 2017 Jul 1;326:15-24. doi: 10.1016/j.taap.2017.04.013. Epub 2017 Apr 13.
12 Formononetin potentiates epirubicin-induced apoptosis via ROS production in HeLa cells in vitro. Chem Biol Interact. 2013 Oct 5;205(3):188-97. doi: 10.1016/j.cbi.2013.07.003. Epub 2013 Jul 16.
13 Relationship between estrogen receptor-binding and estrogenic activities of environmental estrogens and suppression by flavonoids. Biosci Biotechnol Biochem. 2002 Jul;66(7):1479-87. doi: 10.1271/bbb.66.1479.
14 Inhibition of transcription, expression, and secretion of the vascular epithelial growth factor in human epithelial endometriotic cells by romidepsin. Fertil Steril. 2011 Apr;95(5):1579-83. doi: 10.1016/j.fertnstert.2010.12.058. Epub 2011 Feb 4.
15 Inhibitors of class I HDACs and of FLT3 combine synergistically against leukemia cells with mutant FLT3. Arch Toxicol. 2022 Jan;96(1):177-193. doi: 10.1007/s00204-021-03174-1. Epub 2021 Oct 19.
16 Hughes B: 2009 FDA drug approvals. Nat Rev Drug Discov. 2010 Feb;9(2):89-92.
17 Population pharmacokinetics of romidepsin in patients with cutaneous T-cell lymphoma and relapsed peripheral T-cell lymphoma. Clin Cancer Res. 2009 Feb 15;15(4):1496-503.
18 A phase I/II trial of the histone deacetylase inhibitor romidepsin for adults with recurrent malignant glioma: North American Brain Tumor Consortium Study 03-03. Neuro Oncol. 2011 May;13(5):509-16.
19 Population pharmacokinetics of romidepsin in patients with cutaneous T-cell lymphoma and relapsed peripheral T-cell lymphoma. Clin Cancer Res. 2009 Feb 15;15(4):1496-503.
20 FDA Label of Romidepsin. The 2020 official website of the U.S. Food and Drug Administration.
21 Chemoresistance to depsipeptide FK228 [(E)-(1S,4S,10S,21R)-7-[(Z)-ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8,7,6]-tricos-16-ene-3,6,9,22-pentanone] is mediated by reversible MDR1 induction in human cancer cell lines. J Pharmacol Exp Ther. 2005 Jul;314(1):467-75. doi: 10.1124/jpet.105.083956. Epub 2005 Apr 15.
22 Aberrant promoter methylation of the ABCG2 gene in renal carcinoma. Mol Cell Biol. 2006 Nov;26(22):8572-85.
23 5-Aza-2'-deoxycytidine and depsipeptide synergistically induce expression of BIK (BCL2-interacting killer). Biochem Biophys Res Commun. 2006 Dec 15;351(2):455-61. doi: 10.1016/j.bbrc.2006.10.055. Epub 2006 Oct 18.
24 Bortezomib and depsipeptide sensitize tumors to tumor necrosis factor-related apoptosis-inducing ligand: a novel method to potentiate natural killer cell tumor cytotoxicity. Cancer Res. 2006 Jul 15;66(14):7317-25. doi: 10.1158/0008-5472.CAN-06-0680.
25 Histone deacetylase inhibitors FK228, N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl)amino- methyl]benzamide and m-carboxycinnamic acid bis-hydroxamide augment radiation-induced cell death in gastrointestinal adenocarcinoma cells. Int J Cancer. 2004 Jun 10;110(2):301-8. doi: 10.1002/ijc.20117.
26 A sequential treatment of depsipeptide followed by 5-azacytidine enhances Gadd45beta expression in hepatocellular carcinoma cells. Anticancer Res. 2007 Nov-Dec;27(6B):3783-9.
27 Abrogation of p21 expression by flavopiridol enhances depsipeptide-mediated apoptosis in malignant pleural mesothelioma cells. Clin Cancer Res. 2004 Mar 1;10(5):1813-25. doi: 10.1158/1078-0432.ccr-0901-3.
28 Interactions between bortezomib and romidepsin and belinostat in chronic lymphocytic leukemia cells. Clin Cancer Res. 2008 Jan 15;14(2):549-58. doi: 10.1158/1078-0432.CCR-07-1934.
29 Blocking downstream signaling pathways in the context of HDAC inhibition promotes apoptosis preferentially in cells harboring mutant Ras. Oncotarget. 2016 Oct 25;7(43):69804-69815. doi: 10.18632/oncotarget.12001.
30 Up-regulation of MDR1 and induction of doxorubicin resistance by histone deacetylase inhibitor depsipeptide (FK228) and ATRA in acute promyelocytic leukemia cells. Blood. 2006 Feb 15;107(4):1546-54. doi: 10.1182/blood-2004-10-4126. Epub 2005 Oct 13.
31 Antitumor effects of histone deacetylase inhibitor on Ewing's family tumors. Int J Cancer. 2005 Sep 20;116(5):784-92. doi: 10.1002/ijc.21069.
32 Enhanced transgene expression in urothelial cancer gene therapy with histone deacetylase inhibitor. J Urol. 2005 Aug;174(2):747-52. doi: 10.1097/01.ju.0000164723.20555.e6.
33 Enhancement of sodium/iodide symporter expression in thyroid and breast cancer. Endocr Relat Cancer. 2006 Sep;13(3):797-826. doi: 10.1677/erc.1.01143.
34 Identification of cytochrome P450 enzymes involved in the metabolism of FK228, a potent histone deacetylase inhibitor, in human liver microsomes. Biol Pharm Bull. 2005 Jan;28(1):124-9.
35 Involvement of P-glycoprotein and MRP1 in resistance to cyclic tetrapeptide subfamily of histone deacetylase inhibitors in the drug-resistant osteosarcoma and Ewing's sarcoma cells. Int J Cancer. 2006 Jan 1;118(1):90-7. doi: 10.1002/ijc.21297.