Details of the Drug Combination

General Information of Drug Combination (ID: DCF750H)

• Drug Combination Name: I3C + Silibinin
• Indication: Smoking; Status: Phase 1 [1]
• Component Drugs:
  I3C (DMIGFOR): Small molecular drug
  Silibinin (DMSH4DG): N.A.

Molecular Interaction Atlas of This Drug Combination

Indication(s) of I3C

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Phase 3	[2]

I3C Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
NF-kappa-B inhibitor alpha (NFKBIA)	TTSHAEB	IKBA_HUMAN	Inhibitor	[7]

I3C Interacts with 50 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Increases Expression	[8]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Increases Expression	[8]
Aryl hydrocarbon receptor (AHR)	OTFE4EYE	AHR_HUMAN	Increases Expression	[9]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[9]
Cytochrome P450 2E1 (CYP2E1)	OTHQ17JG	CP2E1_HUMAN	Decreases Activity	[10]
Cytochrome P450 2A6 (CYP2A6)	OT52TWG3	CP2A6_HUMAN	Decreases Activity	[10]
T-lymphocyte activation antigen CD86 (CD86)	OTJCSBPC	CD86_HUMAN	Decreases Expression	[11]
C-C chemokine receptor type 5 (CCR5)	OTP5FMZ4	CCR5_HUMAN	Increases Expression	[11]
CD83 antigen (CD83)	OT1V4WQF	CD83_HUMAN	Decreases Expression	[11]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases Expression	[12]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[6]
CASP8 and FADD-like apoptosis regulator (CFLAR)	OTX14BAS	CFLAR_HUMAN	Decreases Expression	[6]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Decreases Expression	[4]
Urokinase-type plasminogen activator (PLAU)	OTX0QGKK	UROK_HUMAN	Increases Expression	[4]
Estrogen receptor (ESR1)	OTKLU61J	ESR1_HUMAN	Decreases Expression	[13]
Trefoil factor 1 (TFF1)	OTCYQH4F	TFF1_HUMAN	Decreases Expression	[14]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Decreases Expression	[5]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Increases Expression	[4]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases Expression	[5]
Cathepsin D (CTSD)	OTQZ36F3	CATD_HUMAN	Decreases Expression	[14]
Transcription factor Sp1 (SP1)	OTISPT4X	SP1_HUMAN	Decreases Activity	[6]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Expression	[6]
Androgen receptor (AR)	OTUBKAZZ	ANDR_HUMAN	Decreases Activity	[6]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[6]
Cyclin-dependent kinase 4 (CDK4)	OT7EP05T	CDK4_HUMAN	Decreases Activity	[13]
NAD(P)H dehydrogenase 1 (NQO1)	OTZGGIVK	NQO1_HUMAN	Increases Expression	[15]
Mucin-1 (MUC1)	OTHQI7IY	MUC1_HUMAN	Decreases Expression	[16]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Decreases Activity	[17]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[6]
G1/S-specific cyclin-E1 (CCNE1)	OTLD7UID	CCNE1_HUMAN	Decreases Expression	[6]
Cyclin-dependent kinase 2 (CDK2)	OTB5DYYZ	CDK2_HUMAN	Decreases Activity	[18]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Decreases Expression	[15]
Breast cancer type 1 susceptibility protein (BRCA1)	OT5BN6VH	BRCA1_HUMAN	Increases Expression	[19]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Decreases Expression	[5]
Cyclin-dependent kinase 4 inhibitor B (CDKN2B)	OTAG24N1	CDN2B_HUMAN	Increases Expression	[6]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Increases Expression	[13]
Breast cancer type 2 susceptibility protein (BRCA2)	OTF1XSV1	BRCA2_HUMAN	Increases Expression	[19]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Decreases Expression	[5]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[6]
Cytochrome c (CYCS)	OTBFALJD	CYC_HUMAN	Affects Localization	[6]
Cyclin-dependent kinase 6 (CDK6)	OTR95N0X	CDK6_HUMAN	Decreases Expression	[18]
Heat shock factor protein 1 (HSF1)	OTYNJ4KP	HSF1_HUMAN	Increases Activity	[20]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Decreases Expression	[15]
Peroxiredoxin-1 (PRDX1)	OTZ3BEC4	PRDX1_HUMAN	Decreases Expression	[5]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[6]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[5]
Nuclear receptor subfamily 1 group I member 3 (NR1I3)	OTS3SGH7	NR1I3_HUMAN	Increases Activity	[21]
Nuclear factor erythroid 2-related factor 2 (NFE2L2)	OT0HENJ5	NF2L2_HUMAN	Decreases Activity	[6]
Growth/differentiation factor 15 (GDF15)	OTWQN50N	GDF15_HUMAN	Increases Expression	[22]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Increases Expression	[23]

Indication(s) of Silibinin

Disease Entry	ICD 11	Status	REF
Hepatic failure	DB99.7	Phase 2/3	[3]

References

• [1] ClinicalTrials.gov (NCT03687073) Trial of Indole-3-Carbinol and Silibinin
• [2] ClinicalTrials.gov (NCT02525159) Effectiveness of DIM Supplements to Increase 2-OHE1/16 Ratio (EDIMI216OHE1). U.S. National Institutes of Health.
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] Extended treatment with physiologic concentrations of dietary phytochemicals results in altered gene expression, reduced growth, and apoptosis of cancer cells. Mol Cancer Ther. 2007 Nov;6(11):3071-9. doi: 10.1158/1535-7163.MCT-07-0117.
• [5] Anticarcinogenic effect of indole-3-carbinol (I3C) on human hepatocellular carcinoma SNU449 cells. Hum Exp Toxicol. 2019 Jan;38(1):136-147. doi: 10.1177/0960327118785235. Epub 2018 Jul 11.
• [6] Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. Cell Cycle. 2005 Sep;4(9):1201-15. doi: 10.4161/cc.4.9.1993. Epub 2005 Sep 6.
• [7] Protective effect of Indole-3-carbinol, an NF-B inhibitor in experimental paradigm of Parkinson's disease: In silico and in vivo studies. Brain Behav Immun. 2020 Nov;90:108-137.
• [8] Induction of phase-1 metabolizing enzymes by oltipraz, flavone and indole-3-carbinol enhance the formation and transport of benzo[a]pyrene sulfate conjugates in intestinal Caco-2 cells. Toxicol Lett. 2005 Aug 14;158(2):140-51.
• [9] The effect of indole-3-carbinol on the expression of CYP1A1, CYP1B1 and AhR genes and proliferation of MCF-7 cells. Acta Biochim Pol. 2007;54(1):113-7.
• [10] Protective effects of isothiocyanates alone or in combination with vitamin C towards N-nitrosodibutylamine or N-nitrosopiperidine-induced oxidative DNA damage in the single-cell gel electrophoresis (SCGE)/HepG2 assay. J Appl Toxicol. 2008 Mar;28(2):196-204.
• [11] Aryl hydrocarbon receptor signaling modifies Toll-like receptor-regulated responses in human dendritic cells. Arch Toxicol. 2017 May;91(5):2209-2221.
• [12] In vitro analysis of factors influencing CYP1A2 expression as potential determinants of interindividual variation. Pharmacol Res Perspect. 2017 Mar 2;5(2):e00299.
• [13] 1-Benzyl-indole-3-carbinol is a novel indole-3-carbinol derivative with significantly enhanced potency of anti-proliferative and anti-estrogenic properties in human breast cancer cells. Chem Biol Interact. 2010 Aug 5;186(3):255-66. doi: 10.1016/j.cbi.2010.05.015. Epub 2010 Jun 2.
• [14] Indole-3-carbinol is a negative regulator of estrogen receptor-alpha signaling in human tumor cells. J Nutr. 2000 Dec;130(12):2927-31. doi: 10.1093/jn/130.12.2927.
• [15] Combination of xanthohumol and phenethyl isothiocyanate inhibits NF-B and activates Nrf2 in pancreatic cancer cells. Toxicol In Vitro. 2020 Jun;65:104799. doi: 10.1016/j.tiv.2020.104799. Epub 2020 Feb 15.
• [16] Inhibition of MUC1 expression by indole-3-carbinol. Int J Cancer. 2004 May 10;109(6):810-6. doi: 10.1002/ijc.20031.
• [17] Indole-3-carbinol suppresses NF-kappaB and IkappaBalpha kinase activation, causing inhibition of expression of NF-kappaB-regulated antiapoptotic and metastatic gene products and enhancement of apoptosis in myeloid and leukemia cells. Blood. 2005 Jul 15;106(2):641-9. doi: 10.1182/blood-2004-12-4589. Epub 2005 Apr 5.
• [18] N-Alkoxy derivatization of indole-3-carbinol increases the efficacy of the G1 cell cycle arrest and of I3C-specific regulation of cell cycle gene transcription and activity in human breast cancer cells. Biochem Pharmacol. 2008 Feb 1;75(3):713-24. doi: 10.1016/j.bcp.2007.09.024. Epub 2007 Oct 2.
• [19] BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells. Br J Cancer. 2006 Feb 13;94(3):407-26. doi: 10.1038/sj.bjc.6602935.
• [20] A Gene Expression Biomarker Predicts Heat Shock Factor 1 Activation in a Gene Expression Compendium. Chem Res Toxicol. 2021 Jul 19;34(7):1721-1737. doi: 10.1021/acs.chemrestox.0c00510. Epub 2021 Jun 25.
• [21] Agonistic effects of diverse xenobiotics on the constitutive androstane receptor as detected in a recombinant yeast-cell assay. Toxicol In Vitro. 2018 Feb;46:335-349. doi: 10.1016/j.tiv.2017.09.014. Epub 2017 Sep 18.
• [22] Indole-3-carbinol and 3,3'-diindolylmethane induce expression of NAG-1 in a p53-independent manner. Biochem Biophys Res Commun. 2005 Mar 4;328(1):63-9. doi: 10.1016/j.bbrc.2004.12.138.
• [23] Phytochemicals induce breast cancer resistance protein in Caco-2 cells and enhance the transport of benzo[a]pyrene-3-sulfate. Toxicol Sci. 2007 Apr;96(2):227-36. doi: 10.1093/toxsci/kfl147. Epub 2006 Oct 31.