Details of the Drug Combination

General Information of Drug Combination (ID: DCSC8U0)

• Drug Combination Name: Pazopanib + Acitretin
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Pazopanib (DMF57DM): N.A.
  Acitretin (DM8BKU9): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 12.07
  Bliss Independence Score: 12.07
  Loewe Additivity Score: 27.79
  LHighest Single Agent (HSA) Score: 27.83

Molecular Interaction Atlas of This Drug Combination

Pazopanib Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[4]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[4]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[5]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[4]

Pazopanib Interacts with 12 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[6]
Cytochrome P450 2C8 (CYP2C8)	OTHCWT42	CP2C8_HUMAN	Increases Expression	[6]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[7]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Increases Expression	[6]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Secretion	[8]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[9]
Phosphatidylcholine translocator ABCB4 (ABCB4)	OTE6PY83	MDR3_HUMAN	Decreases Activity	[10]
Myeloblastin (PRTN3)	OT72MHP7	PRTN3_HUMAN	Increases Expression	[8]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[11]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[11]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[9]
HLA class I histocompatibility antigen protein P5 (HCP5)	OTV0YRI8	HCP5_HUMAN	Increases ADR	[12]

Indication(s) of Acitretin

Disease Entry	ICD 11	Status	REF
Psoriasis vulgaris	EA90	Approved	[2]

Acitretin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Signal transducer and activator of transcription 3 (STAT3)	TTH8FZW	STAT3_HUMAN	Inhibitor	[13]

Acitretin Interacts with 14 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[9]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Activity	[14]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[15]
Retinoic acid receptor RXR-alpha (RXRA)	OTP1TBDM	RXRA_HUMAN	Affects Binding	[16]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[17]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[14]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Expression	[17]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Expression	[17]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[18]
Tumor necrosis factor ligand superfamily member 6 (FASLG)	OTZARCHH	TNFL6_HUMAN	Increases Expression	[14]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[14]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[15]
FAS-associated death domain protein (FADD)	OTV7GFHH	FADD_HUMAN	Increases Expression	[14]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[14]

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: 7598).
• [3] Pazopanib-induced hyperbilirubinemia is associated with Gilbert's syndrome UGT1A1 polymorphism. Br J Cancer. 2010 Apr 27;102(9):1371-7. doi: 10.1038/sj.bjc.6605653. Epub 2010 Apr 13.
• [4] Pazopanib, a new therapy for metastatic soft tissue sarcoma. Expert Opin Pharmacother. 2013 May;14(7):929-35.
• [5] Pazopanib: the newest tyrosine kinase inhibitor for the treatment of advanced or metastatic renal cell carcinoma. Drugs. 2011 Mar 5;71(4):443-54.
• [6] Identification of approved drugs as potent inhibitors of pregnane X receptor activation with differential receptor interaction profiles. Arch Toxicol. 2018 Apr;92(4):1435-1451.
• [7] 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.
• [8] Activation of inflammasomes by tyrosine kinase inhibitors of vascular endothelial growth factor receptor: Implications for VEGFR TKIs-induced immune related adverse events. Toxicol In Vitro. 2021 Mar;71:105063. doi: 10.1016/j.tiv.2020.105063. Epub 2020 Dec 1.
• [9] Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.
• [10] Evaluating the Role of Multidrug Resistance Protein 3 (MDR3) Inhibition in Predicting Drug-Induced Liver Injury Using 125 Pharmaceuticals. Chem Res Toxicol. 2017 May 15;30(5):1219-1229. doi: 10.1021/acs.chemrestox.7b00048. Epub 2017 May 4.
• [11] MEK inhibition abrogates sunitinib resistance in a renal cell carcinoma patient-derived xenograft model. Br J Cancer. 2016 Oct 11;115(8):920-928. doi: 10.1038/bjc.2016.263. Epub 2016 Aug 25.
• [12] HLA-B*57:01 Confers Susceptibility to Pazopanib-Associated Liver Injury in Patients with Cancer. Clin Cancer Res. 2016 Mar 15;22(6):1371-7. doi: 10.1158/1078-0432.CCR-15-2044. Epub 2015 Nov 6.
• [13] Effects of acitretin on the expression of signaling pathway-related genes in epidermal squamous-cell carcinoma cells. Zhonghua Zhong Liu Za Zhi. 2006 Jan;28(1):21-4.
• [14] Acitretin induces apoptosis through CD95 signalling pathway in human cutaneous squamous cell carcinoma cell line SCL-1. J Cell Mol Med. 2009 Sep;13(9A):2888-98. doi: 10.1111/j.1582-4934.2008.00397.x. Epub 2009 Jun 20.
• [15] [Effects of all-trans-retinoic acid, acitretin and tazarotene on apoptosis and Bax/Bcl-2 expressions of human melanoma cells A375 and the significance]. Di Yi Jun Yi Da Xue Xue Bao. 2005 Aug;25(8):972-4, 978.
• [16] Limited Chemical Structural Diversity Found to Modulate Thyroid Hormone Receptor in the Tox21 Chemical Library. Environ Health Perspect. 2019 Sep;127(9):97009. doi: 10.1289/EHP5314. Epub 2019 Sep 30.
• [17] [Acitretin induces apoptosis and changes of relative signaling pathway in epidermoid carcinoma cell line A431]. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2006 Mar;35(2):182-8. doi: 10.3785/j.issn.1008-9292.2006.02.013.
• [18] Effects of ATRA, acitretin and tazarotene on growth and apoptosis of Tca8113 cells. J Huazhong Univ Sci Technolog Med Sci. 2005;25(4):393-6. doi: 10.1007/BF02828205.