Details of the Drug Combination

General Information of Drug Combination (ID: DCGKP0J)

• Drug Combination Name: Methoxsalen + Bexarotene
• Indication: Lymphoma; Status: Phase 1 [1]
• Component Drugs:
  Methoxsalen (DME8FZ9): Small molecular drug
  Bexarotene (DMOBIKY): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Methoxsalen

Disease Entry	ICD 11	Status	REF
Cutaneous T-cell lymphoma	2B01	Approved	[2]
Primary cutaneous T-cell lymphoma	N.A.	Approved	[3]
Psoriasis vulgaris	EA90	Approved	[2]

Methoxsalen Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2A6 (CYP2A6)	TTAQ6ZW	CP2A6_HUMAN	Binder	[7]

Methoxsalen Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[8]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[9]

Methoxsalen Interacts with 26 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2A6 (CYP2A6)	OT52TWG3	CP2A6_HUMAN	Decreases Activity	[10]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[8]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Decreases Activity	[11]
Cocaine esterase (CES2)	OTC647SQ	EST2_HUMAN	Increases Expression	[8]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[8]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Decreases Activity	[12]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Decreases Activity	[12]
Class E basic helix-loop-helix protein 40 (BHLHE40)	OTITX14U	BHE40_HUMAN	Decreases Expression	[13]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[13]
ATP-binding cassette sub-family C member 3 (ABCC3)	OTC3IJV4	MRP3_HUMAN	Increases Expression	[6]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Expression	[14]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[13]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[15]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[16]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[13]
Phosphatidylcholine translocator ABCB4 (ABCB4)	OTE6PY83	MDR3_HUMAN	Decreases Expression	[17]
Cytochrome P450 7A1 (CYP7A1)	OT8Z5KLD	CP7A1_HUMAN	Decreases Expression	[6]
Multidrug resistance-associated protein 1 (ABCC1)	OTGUN89S	MRP1_HUMAN	Increases Expression	[16]
Histidine ammonia-lyase (HAL)	OT1HXFCV	HUTH_HUMAN	Decreases Activity	[18]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Decreases Expression	[13]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[13]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Decreases Expression	[13]
Nuclear receptor subfamily 0 group B member 2 (NR0B2)	OT7UVICX	NR0B2_HUMAN	Increases Expression	[6]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[15]
ATP-binding cassette sub-family C member 2 (ABCC2)	OTJSIGV5	MRP2_HUMAN	Decreases Expression	[16]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Increases Expression	[16]

Indication(s) of Bexarotene

Disease Entry	ICD 11	Status	REF
Cutaneous T-cell lymphoma	2B01	Approved	[4]
Plasma cell myeloma	2A83.1	Approved	[5]
Primary cutaneous T-cell lymphoma	N.A.	Approved	[5]
Schizoaffective disorder	6A21	Approved	[5]

Bexarotene Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Retinoic acid receptor RXR-alpha (RXRA)	TT6PEUO	RXRA_HUMAN	Modulator	[20]

Bexarotene Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[21]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[21]

Bexarotene Interacts with 86 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Retinoic acid receptor RXR-alpha (RXRA)	OTP1TBDM	RXRA_HUMAN	Affects Binding	[22]
Keratin, type I cytoskeletal 14 (KRT14)	OTUVZ1DW	K1C14_HUMAN	Decreases Expression	[23]
Involucrin (IVL)	OT4VPNGY	INVO_HUMAN	Decreases Expression	[23]
Keratin, type II cytoskeletal 5 (KRT5)	OTVGI9HT	K2C5_HUMAN	Decreases Expression	[23]
Protein-glutamine gamma-glutamyltransferase K (TGM1)	OTB8URRI	TGM1_HUMAN	Decreases Expression	[23]
Procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2)	OTKOZRZP	PLOD2_HUMAN	Increases Expression	[19]
CCN family member 1 (CCN1)	OTKJBEMD	CCN1_HUMAN	Decreases Expression	[19]
Stearoyl-CoA desaturase (SCD)	OTB1073G	SCD_HUMAN	Increases Expression	[19]
Period circadian protein homolog 2 (PER2)	OTU2B1DJ	PER2_HUMAN	Decreases Expression	[19]
Cytochrome P450 26A1 (CYP26A1)	OTL1DFWV	CP26A_HUMAN	Increases Expression	[19]
E3 ubiquitin-protein ligase SIAH2 (SIAH2)	OTKED2XN	SIAH2_HUMAN	Decreases Expression	[19]
Integral membrane protein 2A (ITM2A)	OT590V63	ITM2A_HUMAN	Increases Expression	[19]
Transcription factor Maf (MAF)	OT1GR3IZ	MAF_HUMAN	Increases Expression	[19]
Short-chain dehydrogenase/reductase 3 (DHRS3)	OTSK1DTP	DHRS3_HUMAN	Increases Expression	[19]
PRA1 family protein 3 (ARL6IP5)	OTYZ6BEQ	PRAF3_HUMAN	Increases Expression	[19]
Dickkopf-related protein 1 (DKK1)	OTRDLUSP	DKK1_HUMAN	Increases Expression	[19]
Cytochrome c oxidase subunit 2 (COX2)	OTTMVBJJ	COX2_HUMAN	Decreases Expression	[19]
Tissue-type plasminogen activator (PLAT)	OTQPDNAB	TPA_HUMAN	Increases Expression	[19]
Interstitial collagenase (MMP1)	OTI4I2V1	MMP1_HUMAN	Decreases Expression	[19]
Protein S100-A9 (S100A9)	OTOARHCS	S10A9_HUMAN	Increases Expression	[19]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Decreases Expression	[19]
Asparagine synthetase (ASNS)	OT8R922G	ASNS_HUMAN	Decreases Expression	[19]
SPARC (SPARC)	OTPN90H0	SPRC_HUMAN	Increases Expression	[19]
Pro-cathepsin H (CTSH)	OTLFL0DG	CATH_HUMAN	Increases Expression	[19]
Retinoic acid receptor beta (RARB)	OT367U3E	RARB_HUMAN	Increases Expression	[19]
Ornithine decarboxylase (ODC1)	OTNDAGRR	DCOR_HUMAN	Decreases Expression	[19]
Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial (MTHFD2)	OT1LQSGX	MTDC_HUMAN	Decreases Expression	[19]
Integrin beta-6 (ITGB6)	OTI3DJ7U	ITB6_HUMAN	Increases Expression	[19]
Keratin, type I cytoskeletal 15 (KRT15)	OTS6WLF7	K1C15_HUMAN	Increases Expression	[19]
Protein-glutamine gamma-glutamyltransferase 2 (TGM2)	OT6MFOWF	TGM2_HUMAN	Increases Expression	[19]
Insulin-like growth factor-binding protein 6 (IGFBP6)	OTW878VI	IBP6_HUMAN	Increases Expression	[19]
Dual specificity protein phosphatase 1 (DUSP1)	OTN6BR75	DUS1_HUMAN	Decreases Expression	[19]
Ephrin type-A receptor 2 (EPHA2)	OTI6QNX2	EPHA2_HUMAN	Decreases Expression	[19]
Transmembrane 4 L6 family member 1 (TM4SF1)	OTY0ECQN	T4S1_HUMAN	Increases Expression	[19]
High affinity cationic amino acid transporter 1 (SLC7A1)	OTR2ZVA8	CTR1_HUMAN	Decreases Expression	[19]
Cystathionine gamma-lyase (CTH)	OTC90LA0	CGL_HUMAN	Decreases Expression	[19]
Interleukin-15 (IL15)	OTQSYWQS	IL15_HUMAN	Increases Expression	[19]
DNA-binding protein inhibitor ID-1 (ID1)	OTKGNZN5	ID1_HUMAN	Increases Expression	[19]
Glycine--tRNA ligase (GARS1)	OT5B6R9Y	GARS_HUMAN	Decreases Expression	[19]
Eukaryotic translation initiation factor 1 (EIF1)	OTB4GZ0V	EIF1_HUMAN	Decreases Expression	[19]
Aldo-keto reductase family 1 member C3 (AKR1C3)	OTU2SXBA	AK1C3_HUMAN	Increases Expression	[19]
CCAAT/enhancer-binding protein gamma (CEBPG)	OTGNAX3H	CEBPG_HUMAN	Decreases Expression	[19]
Cytochrome c (CYCS)	OTBFALJD	CYC_HUMAN	Decreases Expression	[19]
Serine/arginine-rich splicing factor 2 (SRSF2)	OTVDHO6U	SRSF2_HUMAN	Decreases Expression	[19]
Large neutral amino acids transporter small subunit 1 (SLC7A5)	OT2WPVXD	LAT1_HUMAN	Decreases Expression	[19]
Urokinase plasminogen activator surface receptor (PLAUR)	OTIRKKEQ	UPAR_HUMAN	Decreases Expression	[19]
Keratin, type I cytoskeletal 17 (KRT17)	OT6Y1DPK	K1C17_HUMAN	Decreases Expression	[19]
Aldo-keto reductase family 1 member C1 (AKR1C1)	OTQKR4CM	AK1C1_HUMAN	Increases Expression	[19]
Early growth response protein 3 (EGR3)	OTGPJIRA	EGR3_HUMAN	Decreases Expression	[19]
Proline-rich nuclear receptor coactivator 1 (PNRC1)	OTQMLEE1	PNRC1_HUMAN	Increases Expression	[19]
BCL2/adenovirus E1B 19 kDa protein-interacting protein 2 (BNIP2)	OTVZD4H6	BNIP2_HUMAN	Decreases Expression	[19]
Protein AF1q (MLLT11)	OTG5RVHC	AF1Q_HUMAN	Increases Expression	[19]
Krueppel-like factor 10 (KLF10)	OT4F4UGS	KLF10_HUMAN	Decreases Expression	[19]
Neuronal membrane glycoprotein M6-b (GPM6B)	OT8Q1582	GPM6B_HUMAN	Increases Expression	[19]
Inositol 1,4,5-trisphosphate receptor type 1 (ITPR1)	OTX7MWW1	ITPR1_HUMAN	Increases Expression	[19]
Homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1 protein (HERPUD1)	OT9EROL6	HERP1_HUMAN	Decreases Expression	[19]
Adipogenesis regulatory factor (ADIRF)	OTTJP8D4	ADIRF_HUMAN	Increases Expression	[19]
Dual specificity protein phosphatase 5 (DUSP5)	OTH96RA7	DUS5_HUMAN	Decreases Expression	[19]
TSC22 domain family protein 3 (TSC22D3)	OT03UM03	T22D3_HUMAN	Increases Expression	[19]
Mothers against decapentaplegic homolog 5 (SMAD5)	OTQNSVCQ	SMAD5_HUMAN	Increases Expression	[19]
Immediate early response gene 2 protein (IER2)	OT5OY8BO	IER2_HUMAN	Decreases Expression	[19]
RNA-binding protein PNO1 (PNO1)	OT010GIS	PNO1_HUMAN	Decreases Expression	[19]
Protein DEPP1 (DEPP1)	OTB36PHJ	DEPP1_HUMAN	Increases Expression	[19]
DNA damage-inducible transcript 4 protein (DDIT4)	OTHY8SY4	DDIT4_HUMAN	Increases Expression	[19]
Gamma-adducin (ADD3)	OTDRSHAZ	ADDG_HUMAN	Increases Expression	[19]
Transcription factor MafF (MAFF)	OT9B7MX0	MAFF_HUMAN	Decreases Expression	[19]
Angiomotin-like protein 2 (AMOTL2)	OTRCTKV9	AMOL2_HUMAN	Decreases Expression	[19]
Lysyl oxidase homolog 2 (LOXL2)	OTRT46B5	LOXL2_HUMAN	Increases Expression	[19]
Tumor protein p73 (TP73)	OT0LUO47	P73_HUMAN	Increases Expression	[24]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[24]
Apolipoprotein A-II (APOA2)	OTQ3HGTC	APOA2_HUMAN	Increases Expression	[25]
Interleukin-4 (IL4)	OTOXBWAU	IL4_HUMAN	Decreases Expression	[26]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Phosphorylation	[27]
Cyclin-dependent kinase 1 (CDK1)	OTW1SC2N	CDK1_HUMAN	Decreases Expression	[24]
G2/mitotic-specific cyclin-B1 (CCNB1)	OT19S7E5	CCNB1_HUMAN	Decreases Expression	[24]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Increases Expression	[28]
Retinoic acid receptor RXR-beta (RXRB)	OTNPDXG2	RXRB_HUMAN	Affects Binding	[22]
Sterol regulatory element-binding protein 1 (SREBF1)	OTWBRPAI	SRBP1_HUMAN	Increases Expression	[29]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[24]
Retinoic acid receptor RXR-gamma (RXRG)	OT254B09	RXRG_HUMAN	Affects Binding	[22]
11-beta-hydroxysteroid dehydrogenase type 2 (HSD11B2)	OTHF4H9U	DHI2_HUMAN	Increases Expression	[30]
Oxysterols receptor LXR-alpha (NR1H3)	OT54YZ9I	NR1H3_HUMAN	Decreases Expression	[29]
Serine-protein kinase ATM (ATM)	OTQVOHLT	ATM_HUMAN	Increases Activity	[24]
Krueppel-like factor 9 (KLF9)	OTBFEJRQ	KLF9_HUMAN	Increases Expression	[31]
Sonic hedgehog protein (SHH)	OTOG2BXF	SHH_HUMAN	Increases Expression	[31]
Nuclear receptor subfamily 0 group B member 2 (NR0B2)	OT7UVICX	NR0B2_HUMAN	Increases Expression	[29]

References

• [1] ClinicalTrials.gov (NCT00056056) Ultraviolet Light Therapy Using Methoxsalen With or Without Bexarotene in Treating Patients With Mycosis Fungoides
• [2] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 009048.
• [3] Methoxsalen FDA Label
• [4] 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: 2807).
• [5] Bexarotene FDA Label
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• [16] ABC-transporter blockage mediated by xanthotoxin and bergapten is the major pathway for chemosensitization of multidrug-resistant cancer cells. Toxicol Appl Pharmacol. 2017 Dec 15;337:22-29. doi: 10.1016/j.taap.2017.10.018. Epub 2017 Oct 25.
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• [18] Inhibition of histidine ammonia lyase by 8-methoxypsoralen and psoralen-oxidized photoproducts. Photochem Photobiol. 2010 Nov-Dec;86(6):1272-7. doi: 10.1111/j.1751-1097.2010.00807.x. Epub 2010 Sep 29.
• [19] Identification of biomarkers modulated by the rexinoid LGD1069 (bexarotene) in human breast cells using oligonucleotide arrays. Cancer Res. 2006 Dec 15;66(24):12009-18.
• [20] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [21] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [22] Phthalates efficiently bind to human peroxisome proliferator activated receptor and retinoid X receptor , , subtypes: an in silico approach. J Appl Toxicol. 2014 Jul;34(7):754-65. doi: 10.1002/jat.2902. Epub 2013 Jul 11.
• [23] Retinoic acid receptor- and retinoid X receptor-selective retinoids activate signaling pathways that converge on AP-1 and inhibit squamous differentiation in human bronchial epithelial cells. Cell Growth Differ. 1996 Aug;7(8):997-1004.
• [24] Bexarotene activates the p53/p73 pathway in human cutaneous T-cell lymphoma. Br J Dermatol. 2009 Mar;160(3):519-26. doi: 10.1111/j.1365-2133.2008.08931.x. Epub 2008 Nov 25.
• [25] Retinoids increase human apolipoprotein A-11 expression through activation of the retinoid X receptor but not the retinoic acid receptor. Mol Cell Biol. 1996 Jul;16(7):3350-60. doi: 10.1128/MCB.16.7.3350.
• [26] Biological effects of bexarotene in cutaneous T-cell lymphoma. Arch Dermatol. 2005 Mar;141(3):315-21. doi: 10.1001/archderm.141.3.315.
• [27] Receptor-selective retinoids inhibit the growth of normal and malignant breast cells by inducing G1 cell cycle blockade. Breast Cancer Res Treat. 2006 Mar;96(2):147-57. doi: 10.1007/s10549-005-9071-1. Epub 2005 Nov 5.
• [28] Identification of novel agonists by high-throughput screening and molecular modelling of human constitutive androstane receptor isoform 3. Arch Toxicol. 2019 Aug;93(8):2247-2264. doi: 10.1007/s00204-019-02495-6. Epub 2019 Jul 16.
• [29] Combinations of LXR and RXR agonists induce triglyceride accumulation in human HepaRG cells in a synergistic manner. Arch Toxicol. 2020 Apr;94(4):1303-1320. doi: 10.1007/s00204-020-02685-7. Epub 2020 Mar 2.
• [30] Tributyltin and triphenyltin induce 11-hydroxysteroid dehydrogenase 2 expression and activity through activation of retinoid X receptor . Toxicol Lett. 2020 Apr 1;322:39-49. doi: 10.1016/j.toxlet.2020.01.001. Epub 2020 Jan 9.
• [31] Pituitary specific retinoid-X receptor ligand interactions with thyroid hormone receptor signaling revealed by high throughput reporter and endogenous gene responses. Toxicol In Vitro. 2015 Oct;29(7):1609-18. doi: 10.1016/j.tiv.2015.06.018. Epub 2015 Jun 19.