Details of the Drug Combination

General Information of Drug Combination (ID: DCUFLUR)

• Drug Combination Name: Gonadorelin + EXISULIND
• Indication: Prostate Cancer; Status: Phase 2 [1]
• Component Drugs:
  Gonadorelin (DMAQ469): Small molecular drug
  EXISULIND (DMBY56U): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Gonadorelin

Disease Entry	ICD 11	Status	REF
Amenorrhea	GA20.0	Approved	[2]
Hypothalamic hypogonadism	5A61.2	Approved	[3]

Gonadorelin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Gonadotropin-releasing hormone receptor (GNRHR)	TT8R70G	GNRHR_HUMAN	Agonist	[5]

Gonadorelin Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Prolyl endopeptidase (PREP)	DEVSCNZ	PPCE_HUMAN	Metabolism	[6]
Thimet oligopeptidase (THOP1)	DE95LJC	THOP1_HUMAN	Metabolism	[7]
Metallo-endopeptidase-like 1 (MMEL1)	DEYCUQ2	MMEL1_HUMAN	Metabolism	[8]

Indication(s) of EXISULIND

Disease Entry	ICD 11	Status	REF
Colorectal cancer	2B91.Z	Phase 3	[4]

EXISULIND Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Phosphodiesterase 5A (PDE5A)	TTJ0IQB	PDE5A_HUMAN	Modulator	[13]

EXISULIND Interacts with 34 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
cGMP-dependent 3',5'-cyclic phosphodiesterase (PDE2A)	OTZESF4H	PDE2A_HUMAN	Decreases Activity	[14]
cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A)	OTT8Q1AP	PDE5A_HUMAN	Decreases Activity	[14]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Decreases Expression	[14]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[15]
Mitogen-activated protein kinase 8 (MAPK8)	OTEREYS5	MK08_HUMAN	Increases Activity	[15]
cGMP-dependent protein kinase 1 (PRKG1)	OTPAS4LF	KGP1_HUMAN	Increases Expression	[16]
Polyunsaturated fatty acid lipoxygenase ALOX15 (ALOX15)	OT0RTR7M	LOX15_HUMAN	Increases Expression	[17]
Transcription factor GATA-6 (GATA6)	OTO2BC0F	GATA6_HUMAN	Decreases Expression	[17]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Increases Expression	[18]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Increases Expression	[18]
Peroxisome proliferator-activated receptor delta (PPARD)	OTI4WTOP	PPARD_HUMAN	Increases Expression	[18]
Peroxisome proliferator-activated receptor alpha (PPARA)	OTK095PP	PPARA_HUMAN	Increases Expression	[18]
Diamine acetyltransferase 1 (SAT1)	OT52AU22	SAT1_HUMAN	Increases Expression	[19]
NAD(P)H dehydrogenase 1 (NQO1)	OTZGGIVK	NQO1_HUMAN	Increases Expression	[10]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[20]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Increases Expression	[20]
Adenosine 5'-monophosphoramidase HINT1 (HINT1)	OTQIR8LF	HINT1_HUMAN	Increases Expression	[20]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[21]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Decreases Expression	[22]
Estrogen receptor (ESR1)	OTKLU61J	ESR1_HUMAN	Decreases Expression	[23]
Receptor tyrosine-protein kinase erbB-2 (ERBB2)	OTOAUNCK	ERBB2_HUMAN	Decreases Expression	[22]
Progesterone receptor (PGR)	OT0FZ3QE	PRGR_HUMAN	Decreases Expression	[23]
Prostate-specific antigen (KLK3)	OTFGSBFJ	KLK3_HUMAN	Decreases Expression	[24]
Tumor necrosis factor receptor superfamily member 16 (NGFR)	OTPKSM49	TNR16_HUMAN	Increases Expression	[25]
Matrilysin (MMP7)	OTVT3SEJ	MMP7_HUMAN	Decreases Expression	[26]
15-hydroxyprostaglandin dehydrogenase (HPGD)	OTYZI6JB	PGDH_HUMAN	Increases Expression	[27]
Receptor tyrosine-protein kinase erbB-3 (ERBB3)	OTRSST0A	ERBB3_HUMAN	Decreases Expression	[22]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[28]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[29]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[29]
Cytochrome P450 4A11 (CYP4A11)	OTPU5J0S	CP4AB_HUMAN	Affects Activity	[30]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Affects Localization	[31]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Increases Expression	[32]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[21]

References

• [1] ClinicalTrials.gov (NCT00283803) Exisulind and Intermittent Androgen Suppression (ADT) in Biochemical Relapsed Prostate Cancer
• [2] Gonadorelin 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: 4391).
• [4] ClinicalTrials.gov (NCT00085826) A Phase III Study of the Efficacy of Taxotere/Aptosyn Versus Taxotere/Placebo in Non-Small Cell Lung Cancer Patients. U.S. National Institutes of Health.
• [5] Use of cognitive behavior therapy for functional hypothalamic amenorrhea. Ann N Y Acad Sci. 2006 Dec;1092:114-29.
• [6] Ion-exchange chromatography: basic principles and application to the partial purification of soluble mammalian prolyl oligopeptidase. Methods Mol Biol. 2011;681:215-28.
• [7] Sleep deprivation changes thimet oligopeptidase (THOP1) expression and activity in rat brain. Heliyon. 2019 Nov 26;5(11):e02896.
• [8] Cell-specific activity of neprilysin 2 isoforms and enzymic specificity compared with neprilysin. Biochem J. 2002 May 1;363(Pt 3):697-705.
• [9] Activation of protein kinase G up-regulates expression of 15-lipoxygenase-1 in human colon cancer cells. Cancer Res. 2005 Sep 15;65(18):8442-7.
• [10] Sulindac and its metabolites induce carcinogen metabolizing enzymes in human colon cancer cells. Int J Cancer. 2008 Mar 1;122(5):990-8.
• [11] Nonsteroidal anti-inflammatory drugs induce colorectal cancer cell apoptosis by suppressing 14-3-3epsilon. Cancer Res. 2007 Apr 1;67(7):3185-91. doi: 10.1158/0008-5472.CAN-06-3431.
• [12] Glucuronidation of nonsteroidal anti-inflammatory drugs: identifying the enzymes responsible in human liver microsomes. Drug Metab Dispos. 2005 Jul;33(7):1027-35.
• [13] Exisulind induction of apoptosis involves guanosine 3',5'-cyclic monophosphate phosphodiesterase inhibition, protein kinase G activation, and attenuated beta-catenin. Cancer Res. 2000 Jul 1;60(13):3338-42.
• [14] Exisulind induction of apoptosis involves guanosine 3',5'-cyclic monophosphate phosphodiesterase inhibition, protein kinase G activation, and attenuated beta-catenin. Cancer Res. 2000 Jul 1;60(13):3338-42.
• [15] Cyclic GMP mediates apoptosis induced by sulindac derivatives via activation of c-Jun NH2-terminal kinase 1. Clin Cancer Res. 2000 Oct;6(10):4136-41.
• [16] Cyclic GMP-dependent protein kinase activation and induction by exisulind and CP461 in colon tumor cells. J Pharmacol Exp Ther. 2001 Nov;299(2):583-92.
• [17] GATA-6 transcriptional regulation of 15-lipoxygenase-1 during NSAID-induced apoptosis in colorectal cancer cells. Cancer Res. 2002 Feb 15;62(4):1178-83.
• [18] PPARgamma-mediated antineoplastic effect of NSAID sulindac on human oral squamous carcinoma cells. Int J Cancer. 2002 Apr 20;98(6):817-23.
• [19] Cyclooxygenase-independent induction of apoptosis by sulindac sulfone is mediated by polyamines in colon cancer. J Biol Chem. 2003 Nov 28;278(48):47762-75.
• [20] Activation of protein kinase G Increases the expression of p21CIP1, p27KIP1, and histidine triad protein 1 through Sp1. Cancer Res. 2008 Jul 1;68(13):5355-62.
• [21] Sulindac sulfide-induced apoptosis involves death receptor 5 and the caspase 8-dependent pathway in human colon and prostate cancer cells. Cancer Res. 2001 Sep 15;61(18):6918-24.
• [22] Sulindac metabolites induce proteosomal and lysosomal degradation of the epidermal growth factor receptor. Cancer Prev Res (Phila). 2010 Apr;3(4):560-72. doi: 10.1158/1940-6207.CAPR-09-0159. Epub 2010 Mar 23.
• [23] Sulindac sulfide and exisulind inhibit expression of the estrogen and progesterone receptors in human breast cancer cells. Clin Cancer Res. 2006 Jun 1;12(11 Pt 1):3478-84. doi: 10.1158/1078-0432.CCR-05-2051.
• [24] Safety and efficacy of exisulind for treatment of recurrent prostate cancer after radical prostatectomy. J Urol. 2001 Sep;166(3):882-6.
• [25] A comparison of the effectiveness of selected non-steroidal anti-inflammatory drugs and their derivatives against cancer cells in vitro. Cancer Chemother Pharmacol. 2008 Feb;61(2):203-14. doi: 10.1007/s00280-007-0462-3. Epub 2007 Apr 20.
• [26] Nobiletin, a citrus flavonoid, down-regulates matrix metalloproteinase-7 (matrilysin) expression in HT-29 human colorectal cancer cells. Biosci Biotechnol Biochem. 2005 Feb;69(2):307-14. doi: 10.1271/bbb.69.307.
• [27] 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is up-regulated by flurbiprofen and other non-steroidal anti-inflammatory drugs in human colon cancer HT29 cells. Arch Biochem Biophys. 2009 Jul 15;487(2):139-45. doi: 10.1016/j.abb.2009.05.017. Epub 2009 Jun 6.
• [28] Pro-apoptotic actions of exisulind and CP461 in SW480 colon tumor cells involve beta-catenin and cyclin D1 down-regulation. Biochem Pharmacol. 2002 Nov 1;64(9):1325-36. doi: 10.1016/s0006-2952(02)01345-x.
• [29] Inhibition of extracellular-signal regulated kinases 1/2 is required for apoptosis of human colon cancer cells in vitro by sulindac metabolites. Cancer Res. 2004 Nov 15;64(22):8148-51. doi: 10.1158/0008-5472.CAN-04-1517.
• [30] Effects of acidic non-steroidal anti-inflammatory drugs on human cytochrome P450 4A11 activity: Roles of carboxylic acid and a sulfur atom in potent inhibition by sulindac sulfide. Chem Biol Interact. 2023 Sep 1;382:110644. doi: 10.1016/j.cbi.2023.110644. Epub 2023 Jul 25.
• [31] The proapoptotic effects of sulindac, sulindac sulfone and indomethacin are mediated by nucleolar translocation of the RelA(p65) subunit of NF-kappaB. Oncogene. 2008 Apr 17;27(18):2648-55. doi: 10.1038/sj.onc.1210891. Epub 2007 Dec 3.
• [32] Sulindac enhances adenoviral vector expressing mda-7/IL-24-mediated apoptosis in human lung cancer. Mol Cancer Ther. 2005 Feb;4(2):291-304.