Details of the Drug Combination

General Information of Drug Combination (ID: DC754VJ)

• Drug Combination Name: Letrozole + Ifosfamide
• Indication: Clear cell renal cell carcinoma; Status: Investigative [1]
• Component Drugs:
  Letrozole (DMH07Y3): Small molecular drug
  Ifosfamide (DMCT3I8): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: TK-10
  Zero Interaction Potency (ZIP) Score: 0.11
  Bliss Independence Score: 1.36
  Loewe Additivity Score: 0.47
  LHighest Single Agent (HSA) Score: 0.55

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Letrozole

Disease Entry	ICD 11	Status	REF
Estrogen-receptor positive breast cancer	N.A.	Approved	[2]
Hormonally-responsive breast cancer	2C60-2C65	Approved	[3]

Letrozole Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Aromatase (CYP19A1)	TTSZLWK	CP19A_HUMAN	Inhibitor	[6]

Letrozole Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]
Aromatase (CYP19A1)	DEQX145	CP19A_HUMAN	Metabolism	[8]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[9]

Letrozole Interacts with 18 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Decreases Activity	[10]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Oxidation	[11]
Cytochrome P450 2A6 (CYP2A6)	OT52TWG3	CP2A6_HUMAN	Increases Oxidation	[11]
Adenylate kinase isoenzyme 1 (AK1)	OT614AR3	KAD1_HUMAN	Increases ADR	[12]
Dickkopf-related protein 1 (DKK1)	OTRDLUSP	DKK1_HUMAN	Increases Expression	[13]
Follitropin subunit beta (FSHB)	OTGLS283	FSHB_HUMAN	Increases Expression	[14]
Lutropin subunit beta (LHB)	OT5GBOVJ	LSHB_HUMAN	Increases Expression	[14]
Progesterone receptor (PGR)	OT0FZ3QE	PRGR_HUMAN	Decreases Expression	[15]
Leukemia inhibitory factor (LIF)	OTO46S5S	LIF_HUMAN	Increases Expression	[13]
Gap junction alpha-1 protein (GJA1)	OTT94MKL	CXA1_HUMAN	Decreases Expression	[16]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[17]
G1/S-specific cyclin-D2 (CCND2)	OTDULQF9	CCND2_HUMAN	Decreases Expression	[17]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[18]
Leukemia inhibitory factor receptor (LIFR)	OT36W9O5	LIFR_HUMAN	Increases Expression	[13]
Proliferation marker protein Ki-67 (MKI67)	OTA8N1QI	KI67_HUMAN	Decreases Expression	[15]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Phosphorylation	[17]
Lanosterol 14-alpha demethylase (CYP51A1)	OTAYHG9C	CP51A_HUMAN	Decreases Activity	[19]
Fibroblast growth factor 22 (FGF22)	OTVIX6J0	FGF22_HUMAN	Increases Expression	[13]

Indication(s) of Ifosfamide

Disease Entry	ICD 11	Status	REF
Adult central nervous system germ cell tumor	N.A.	Approved	[4]
Adult teratoma	N.A.	Approved	[4]
Advanced cancer	2A00-2F9Z	Approved	[4]
Extragonadal germ cell cancer	N.A.	Approved	[4]
Extragonadal germ cell tumor	N.A.	Approved	[4]
Kidney neoplasm	N.A.	Approved	[4]
Solid tumour/cancer	2A00-2F9Z	Approved	[5]
Testicular germ cell tumor	N.A.	Approved	[4]
Extragonadal nonseminomatous germ cell tumor	N.A.	Investigative	[4]
Extragonadal seminoma	N.A.	Investigative	[4]
Neuroblastoma	2D11.2	Investigative	[4]
Retinoblastoma	2D02.2	Investigative	[4]

Ifosfamide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Modulator	[21]

Ifosfamide Interacts with 10 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[22]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[23]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[24]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[25]
Cytochrome P450 2C18 (CYP2C18)	DEZMWRE	CP2CI_HUMAN	Metabolism	[26]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[24]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[27]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[28]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[26]
Prostaglandin G/H synthase 1 (COX-1)	DE073H6	PGH1_HUMAN	Metabolism	[22]

Ifosfamide Interacts with 214 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C8 (CYP2C8)	OTHCWT42	CP2C8_HUMAN	Increases Activity	[29]
Cytochrome P450 2C18 (CYP2C18)	OTY687L9	CP2CI_HUMAN	Increases Activity	[29]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Ethylation	[30]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Decreases Ethylation	[30]
Cytochrome P450 2A6 (CYP2A6)	OT52TWG3	CP2A6_HUMAN	Affects Hydroxylation	[23]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Increases Response To Substance	[31]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Increases Response To Substance	[31]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Increases Response To Substance	[32]
Beta-2-microglobulin (B2M)	OTDWN6NX	B2MG_HUMAN	Increases Expression	[33]
Alpha-2A adrenergic receptor (ADRA2A)	OTZFGOTP	ADA2A_HUMAN	Increases ADR	[12]
Interleukin-19 (IL19)	OT9VGDIP	IL19_HUMAN	Increases Secretion	[34]
Solute carrier family 12 member 8 (SLC12A8)	OTHJP5FU	S12A8_HUMAN	Decreases Expression	[20]
Toll-like receptor 4 (TLR4)	OTP7ML3S	TLR4_HUMAN	Increases Expression	[20]
Agrin (AGRN)	OTWJENAZ	AGRIN_HUMAN	Increases Expression	[20]
Podocalyxin (PODXL)	OTPNQXF3	PODXL_HUMAN	Decreases Expression	[20]
Class E basic helix-loop-helix protein 40 (BHLHE40)	OTITX14U	BHE40_HUMAN	Increases Expression	[20]
TRAF-type zinc finger domain-containing protein 1 (TRAFD1)	OT7AU2R3	TRAD1_HUMAN	Increases Expression	[20]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[20]
Rho guanine nucleotide exchange factor 10 (ARHGEF10)	OTHJ1Y4I	ARHGA_HUMAN	Affects Expression	[20]
Protein phosphatase 1D (PPM1D)	OT8NLZ9D	PPM1D_HUMAN	Decreases Expression	[20]
Apoptosis regulatory protein Siva (SIVA1)	OTDT0XZK	SIVA_HUMAN	Increases Expression	[20]
Transcription factor MafG (MAFG)	OTBQFUZH	MAFG_HUMAN	Increases Expression	[20]
D-3-phosphoglycerate dehydrogenase (PHGDH)	OT1LMRTG	SERA_HUMAN	Increases Expression	[20]
E3 ubiquitin-protein ligase SIAH2 (SIAH2)	OTKED2XN	SIAH2_HUMAN	Increases Expression	[20]
Protein regulator of cytokinesis 1 (PRC1)	OTHD0XS0	PRC1_HUMAN	Increases Expression	[20]
TP53-regulated inhibitor of apoptosis 1 (TRIAP1)	OTEAUJXN	TRIA1_HUMAN	Increases Expression	[20]
5'-AMP-activated protein kinase subunit beta-2 (PRKAB2)	OTLVN68B	AAKB2_HUMAN	Affects Expression	[20]
Mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20)	OT6CLFXB	MCAT_HUMAN	Increases Expression	[20]
NUAK family SNF1-like kinase 1 (NUAK1)	OTLLHJJQ	NUAK1_HUMAN	Decreases Expression	[20]
High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A (PDE8A)	OT4RF9Z4	PDE8A_HUMAN	Decreases Expression	[20]
Mitochondrial import inner membrane translocase subunit Tim17-B (TIMM17B)	OTSQGLSB	TI17B_HUMAN	Decreases Expression	[20]
PR domain zinc finger protein 1 (PRDM1)	OTQLSVBS	PRDM1_HUMAN	Decreases Expression	[20]
E3 ubiquitin-protein ligase listerin (LTN1)	OTIW2HTX	LTN1_HUMAN	Decreases Expression	[20]
Tumor necrosis factor alpha-induced protein 8 (TNFAIP8)	OT1G9297	TFIP8_HUMAN	Increases Expression	[20]
Tetraspanin-12 (TSPAN12)	OTF9I3CX	TSN12_HUMAN	Decreases Expression	[20]
G1/S-specific cyclin-E2 (CCNE2)	OTBBUKQQ	CCNE2_HUMAN	Increases Expression	[20]
Glutathione reductase, mitochondrial (GSR)	OTM2TUYM	GSHR_HUMAN	Increases Expression	[20]
Metallothionein-2 (MT2A)	OTHOACHD	MT2_HUMAN	Increases Expression	[20]
Fructose-bisphosphate aldolase A (ALDOA)	OTWRFTIB	ALDOA_HUMAN	Increases Expression	[20]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Affects Activity	[20]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Expression	[20]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases Expression	[20]
Fatty acid-binding protein, heart (FABP3)	OT562DA1	FABPH_HUMAN	Decreases Expression	[20]
Transcription factor AP-2-alpha (TFAP2A)	OTMYT3NK	AP2A_HUMAN	Decreases Expression	[20]
Integrin beta-1 (ITGB1)	OT6G1IAR	ITB1_HUMAN	Affects Expression	[20]
Glycogen phosphorylase, liver form (PYGL)	OTS1YFGR	PYGL_HUMAN	Decreases Expression	[20]
Amino acid transporter heavy chain SLC3A2 (SLC3A2)	OTBR33M9	4F2_HUMAN	Increases Expression	[20]
Asparagine synthetase (ASNS)	OT8R922G	ASNS_HUMAN	Increases Expression	[20]
Keratin, type I cytoskeletal 19 (KRT19)	OTDGDQ75	K1C19_HUMAN	Increases Expression	[20]
Gamma-enolase (ENO2)	OTRODL0T	ENOG_HUMAN	Increases Expression	[20]
Heat shock 70 kDa protein 1A (HSPA1A)	OTKGIE76	HS71A_HUMAN	Increases Expression	[20]
RNA-binding protein RO60 (RO60)	OTLGM5A8	RO60_HUMAN	Decreases Expression	[20]
Solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1)	OTA675TJ	GTR1_HUMAN	Increases Expression	[20]
DNA topoisomerase 1 (TOP1)	OT51O0CF	TOP1_HUMAN	Increases Expression	[20]
Cation-independent mannose-6-phosphate receptor (IGF2R)	OTDXPQVX	MPRI_HUMAN	Increases Expression	[20]
Prolyl 4-hydroxylase subunit alpha-1 (P4HA1)	OTV04QE5	P4HA1_HUMAN	Decreases Expression	[20]
Fos-related antigen 1 (FOSL1)	OT9YTYMB	FOSL1_HUMAN	Increases Expression	[20]
NAD(P)H dehydrogenase 1 (NQO1)	OTZGGIVK	NQO1_HUMAN	Decreases Expression	[20]
Protein SON (SON)	OT9VWV18	SON_HUMAN	Decreases Expression	[20]
Cyclic AMP-dependent transcription factor ATF-4 (ATF4)	OTRFV19J	ATF4_HUMAN	Affects Activity	[20]
Keratin, type I cytoskeletal 15 (KRT15)	OTS6WLF7	K1C15_HUMAN	Increases Expression	[20]
Ephrin-A1 (EFNA1)	OTU2NUA2	EFNA1_HUMAN	Decreases Expression	[20]
Iduronate 2-sulfatase (IDS)	OTZO94EO	IDS_HUMAN	Decreases Expression	[20]
Ferrochelatase, mitochondrial (FECH)	OTDWEI6C	HEMH_HUMAN	Decreases Expression	[20]
Diacylglycerol kinase alpha (DGKA)	OTTBVNEZ	DGKA_HUMAN	Increases Expression	[20]
Thromboxane-A synthase (TBXAS1)	OTAXZJJ4	THAS_HUMAN	Increases Expression	[20]
Bromodomain-containing protein 2 (BRD2)	OTQP2MVJ	BRD2_HUMAN	Decreases Expression	[20]
DnaJ homolog subfamily B member 2 (DNAJB2)	OTZHPV5M	DNJB2_HUMAN	Increases Expression	[20]
Neuropeptide Y receptor type 1 (NPY1R)	OT5DA9DY	NPY1R_HUMAN	Increases Expression	[20]
Threonine--tRNA ligase 1, cytoplasmic (TARS1)	OT0PWST5	SYTC_HUMAN	Decreases Expression	[20]
Adenylate kinase 4, mitochondrial (AK4)	OTA0T02Q	KAD4_HUMAN	Increases Expression	[20]
ETS domain-containing protein Elk-4 (ELK4)	OTVSSEOE	ELK4_HUMAN	Decreases Expression	[20]
Tyrosine-protein kinase receptor UFO (AXL)	OTKA2SUX	UFO_HUMAN	Increases Expression	[20]
14-3-3 protein sigma (SFN)	OTLJCZ1U	1433S_HUMAN	Increases Expression	[20]
Pyrroline-5-carboxylate reductase 1, mitochondrial (PYCR1)	OTQHB52T	P5CR1_HUMAN	Increases Expression	[20]
Cystathionine gamma-lyase (CTH)	OTC90LA0	CGL_HUMAN	Affects Expression	[20]
Long-chain-fatty-acid--CoA ligase 1 (ACSL1)	OTB06ESI	ACSL1_HUMAN	Decreases Expression	[20]
Thrombospondin-2 (THBS2)	OTXET551	TSP2_HUMAN	Decreases Expression	[20]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[20]
Aryl hydrocarbon receptor (AHR)	OTFE4EYE	AHR_HUMAN	Affects Activity	[20]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Affects Activity	[20]
Transaldolase (TALDO1)	OTDKV2S2	TALDO_HUMAN	Increases Expression	[20]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[20]
Glycine--tRNA ligase (GARS1)	OT5B6R9Y	GARS_HUMAN	Increases Expression	[20]
Isoleucine--tRNA ligase, cytoplasmic (IARS1)	OT9WXH5N	SYIC_HUMAN	Increases Expression	[20]
Tumor necrosis factor ligand superfamily member 9 (TNFSF9)	OTV9L89D	TNFL9_HUMAN	Increases Expression	[20]
Eukaryotic translation initiation factor 1 (EIF1)	OTB4GZ0V	EIF1_HUMAN	Increases Expression	[20]
ATP-binding cassette sub-family G member 1 (ABCG1)	OT5BG6MK	ABCG1_HUMAN	Decreases Expression	[20]
Retinaldehyde dehydrogenase 3 (ALDH1A3)	OT1C9NKQ	AL1A3_HUMAN	Increases Expression	[20]
Sodium- and chloride-dependent glycine transporter 1 (SLC6A9)	OTHRUON2	SC6A9_HUMAN	Decreases Expression	[20]
NADP-dependent malic enzyme (ME1)	OTSVEUQE	MAOX_HUMAN	Decreases Expression	[20]
Glutamate--cysteine ligase catalytic subunit (GCLC)	OTESDI4D	GSH1_HUMAN	Decreases Expression	[20]
Glutamate--cysteine ligase regulatory subunit (GCLM)	OT6CP234	GSH0_HUMAN	Increases Expression	[20]
Cysteine--tRNA ligase, cytoplasmic (CARS1)	OTOUZF6O	SYCC_HUMAN	Decreases Expression	[20]
Serine--tRNA ligase, cytoplasmic (SARS1)	OTFKXQ1O	SYSC_HUMAN	Increases Expression	[20]
Max-interacting protein 1 (MXI1)	OTUQ9E0D	MXI1_HUMAN	Decreases Expression	[20]
Aldo-keto reductase family 1 member C2 (AKR1C2)	OTQ2XMO3	AK1C2_HUMAN	Increases Expression	[20]
Dipeptidyl peptidase 1 (CTSC)	OT79WJZZ	CATC_HUMAN	Increases Expression	[20]
Ataxin-1 (ATXN1)	OTQF0HNR	ATX1_HUMAN	Decreases Expression	[20]
Branched-chain-amino-acid aminotransferase, cytosolic (BCAT1)	OTYHXLWZ	BCAT1_HUMAN	Decreases Expression	[20]
Homeobox protein DLX-1 (DLX1)	OT7BH057	DLX1_HUMAN	Decreases Expression	[20]
Protein BTG2 (BTG2)	OTZF6K1H	BTG2_HUMAN	Increases Expression	[20]
Cyclin-dependent kinase 6 (CDK6)	OTR95N0X	CDK6_HUMAN	Affects Expression	[20]
E3 ubiquitin-protein ligase Mdm2 (MDM2)	OTOVXARF	MDM2_HUMAN	Increases Expression	[20]
Large neutral amino acids transporter small subunit 1 (SLC7A5)	OT2WPVXD	LAT1_HUMAN	Increases Expression	[20]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[20]
Transmembrane protein 94 (TMEM94)	OTT4ZSUA	TMM94_HUMAN	Decreases Expression	[20]
BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)	OT4SO7J4	BNIP3_HUMAN	Decreases Expression	[20]
Zinc finger protein Rlf (RLF)	OTCSPZVK	RLF_HUMAN	Increases Expression	[20]
Peptidyl-prolyl cis-trans isomerase G (PPIG)	OTZ8BTTM	PPIG_HUMAN	Decreases Expression	[20]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Increases Expression	[20]
Ras-related protein Rab-31 (RAB31)	OTMLXQZ0	RAB31_HUMAN	Increases Expression	[20]
Kelch-like ECH-associated protein 1 (KEAP1)	OTFHOD0C	KEAP1_HUMAN	Increases Expression	[20]
Src substrate cortactin (CTTN)	OTJRG4ES	SRC8_HUMAN	Increases Expression	[20]
Enhancer of filamentation 1 (NEDD9)	OTGCFN4M	CASL_HUMAN	Decreases Expression	[20]
Protein disulfide-isomerase A5 (PDIA5)	OT76ZSX5	PDIA5_HUMAN	Increases Expression	[20]
Condensin complex subunit 1 (NCAPD2)	OT8VGE2O	CND1_HUMAN	Increases Expression	[20]
Probable E3 ubiquitin-protein ligase HERC3 (HERC3)	OTWMKYD9	HERC3_HUMAN	Decreases Expression	[20]
kinase isozyme 1, mitochondrial (PDK1)	OTMABK9Z	PDK1_HUMAN	Decreases Expression	[20]
Neutral amino acid transporter B(0) (SLC1A5)	OTE2H26Q	AAAT_HUMAN	Increases Expression	[20]
Nuclear factor erythroid 2-related factor 2 (NFE2L2)	OT0HENJ5	NF2L2_HUMAN	Affects Activity	[20]
Cyclin-G2 (CCNG2)	OTII38K2	CCNG2_HUMAN	Decreases Expression	[20]
Neuronal regeneration-related protein (NREP)	OT2AZPKK	NREP_HUMAN	Affects Expression	[20]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Affects Activity	[20]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Expression	[20]
Laminin subunit alpha-3 (LAMA3)	OTFME7HT	LAMA3_HUMAN	Increases Expression	[20]
Atos homolog protein A (ATOSA)	OTWFM5G0	ATOSA_HUMAN	Decreases Expression	[20]
Glycerol-3-phosphate acyltransferase 3 (GPAT3)	OTJUGPK0	GPAT3_HUMAN	Increases Expression	[20]
Quinone oxidoreductase PIG3 (TP53I3)	OTSCM68G	QORX_HUMAN	Increases Expression	[20]
RRP12-like protein (RRP12)	OTQQAEH4	RRP12_HUMAN	Increases Expression	[20]
ALS2 C-terminal-like protein (ALS2CL)	OT8RY7TZ	AL2CL_HUMAN	Affects Expression	[20]
Dynamin-binding protein (DNMBP)	OTMHH14H	DNMBP_HUMAN	Increases Expression	[20]
Ribosomal protein eS27-like (RPS27L)	OTZWHU0N	RS27L_HUMAN	Increases Expression	[20]
Arginine/serine-rich coiled-coil protein 2 (RSRC2)	OTLE0KQM	RSRC2_HUMAN	Decreases Expression	[20]
Mitochondrial enolase superfamily member 1 (ENOSF1)	OT65D3ZK	ENOF1_HUMAN	Decreases Expression	[20]
Ribonucleoside-diphosphate reductase subunit M2 B (RRM2B)	OTE8GBUR	RIR2B_HUMAN	Decreases Expression	[20]
Protein LYRIC (MTDH)	OTGH7N4C	LYRIC_HUMAN	Decreases Expression	[20]
Liprin-beta-1 (PPFIBP1)	OTRA2S7B	LIPB1_HUMAN	Increases Expression	[20]
Dynein axonemal intermediate chain 3 (DNAI3)	OTG1A0QP	DNAI3_HUMAN	Decreases Expression	[20]
Extracellular sulfatase Sulf-2 (SULF2)	OTIXMUVL	SULF2_HUMAN	Decreases Expression	[20]
Protein O-mannosyl-transferase TMTC2 (TMTC2)	OTY1QWYU	TMTC2_HUMAN	Decreases Expression	[20]
Ninein (NIN)	OTVH3M4Z	NIN_HUMAN	Decreases Expression	[20]
Ceramide synthase 5 (CERS5)	OT5A2DNI	CERS5_HUMAN	Increases Expression	[20]
Uncharacterized protein C8orf58 (C8ORF58)	OTHW01L0	CH058_HUMAN	Increases Expression	[20]
F-box only protein 22 (FBXO22)	OTEJ5MO0	FBX22_HUMAN	Increases Expression	[20]
(Lyso)-N-acylphosphatidylethanolamine lipase (ABHD4)	OTQK3M9X	ABHD4_HUMAN	Increases Expression	[20]
F-box only protein 30 (FBXO30)	OTD1P6LA	FBX30_HUMAN	Decreases Expression	[20]
Pantothenate kinase 1 (PANK1)	OT2CZVRT	PANK1_HUMAN	Decreases Expression	[20]
SH3 domain and tetratricopeptide repeat-containing protein 1 (SH3TC1)	OT0HYZIU	S3TC1_HUMAN	Decreases Expression	[20]
Uncharacterized protein C4orf3 (C4ORF3)	OT6TFN1O	CD003_HUMAN	Decreases Expression	[20]
Paraspeckle component 1 (PSPC1)	OTYS6WQ8	PSPC1_HUMAN	Decreases Expression	[20]
Histone acetyltransferase KAT6B (KAT6B)	OTMUDTAH	KAT6B_HUMAN	Decreases Expression	[20]
E3 ubiquitin-protein ligase rififylin (RFFL)	OT85MGDH	RFFL_HUMAN	Increases Expression	[20]
Probable ATP-dependent RNA helicase DDX17 (DDX17)	OTXRMMBP	DDX17_HUMAN	Decreases Expression	[20]
GTP-binding protein Rit1 (RIT1)	OTVNOGOH	RIT1_HUMAN	Increases Expression	[20]
KICSTOR complex protein ITFG2 (ITFG2)	OT0NLZ8I	ITFG2_HUMAN	Decreases Expression	[20]
Protein TMEPAI (PMEPA1)	OTY8Z9UF	PMEPA_HUMAN	Increases Expression	[20]
Protein FAM162A (FAM162A)	OT882DND	F162A_HUMAN	Decreases Expression	[20]
Tumor protein p53-inducible nuclear protein 1 (TP53INP1)	OT2363Z9	T53I1_HUMAN	Increases Expression	[20]
SPRY domain-containing SOCS box protein 1 (SPSB1)	OTGY26U4	SPSB1_HUMAN	Increases Expression	[20]
Carboxymethylenebutenolidase homolog (CMBL)	OT8H3S3G	CMBL_HUMAN	Increases Expression	[20]
Aurora kinase B (AURKB)	OTIY4VHU	AURKB_HUMAN	Increases Expression	[20]
Protein FAM89A (FAM89A)	OTNASAXT	FA89A_HUMAN	Increases Expression	[20]
ERO1-like protein alpha (ERO1A)	OTVKOQWM	ERO1A_HUMAN	Increases Expression	[20]
Protein FAM210B, mitochondrial (FAM210B)	OT2QHEQ6	F210B_HUMAN	Decreases Expression	[20]
E1A-binding protein p400 (EP400)	OTVQ75NX	EP400_HUMAN	Decreases Expression	[20]
Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2)	OT9C3KFI	KKCC2_HUMAN	Increases Expression	[20]
ETS-related transcription factor Elf-4 (ELF4)	OT167PR5	ELF4_HUMAN	Increases Expression	[20]
Eukaryotic translation initiation factor 3 subunit C (EIF3C)	OTR8RF9X	EIF3C_HUMAN	Decreases Expression	[20]
Growth/differentiation factor 15 (GDF15)	OTWQN50N	GDF15_HUMAN	Increases Expression	[20]
Cancer-related nucleoside-triphosphatase (NTPCR)	OTTRT6Z9	NTPCR_HUMAN	Increases Expression	[20]
G-protein coupled receptor 87 (GPR87)	OTQX45UM	GPR87_HUMAN	Decreases Expression	[20]
Sulfiredoxin-1 (SRXN1)	OTYDBO4L	SRXN1_HUMAN	Increases Expression	[20]
G protein-coupled receptor 88 (GPR88)	OTGAT70V	GPR88_HUMAN	Increases Expression	[20]
Coiled-coil domain-containing protein 90B, mitochondrial (CCDC90B)	OTFFWB0C	CC90B_HUMAN	Decreases Expression	[20]
Polyprenol reductase (SRD5A3)	OT9IJLX7	PORED_HUMAN	Decreases Expression	[20]
E3 ubiquitin ligase RNF121 (RNF121)	OTA0YMLW	RN121_HUMAN	Decreases Expression	[20]
Ankyrin repeat family A protein 2 (ANKRA2)	OTLSLV5A	ANRA2_HUMAN	Decreases Expression	[20]
p53-induced death domain-containing protein 1 (PIDD1)	OTWFM930	PIDD1_HUMAN	Decreases Expression	[20]
ATP-binding cassette sub-family B member 6 (ABCB6)	OTPGZFES	ABCB6_HUMAN	Increases Expression	[20]
ABC-type oligopeptide transporter ABCB9 (ABCB9)	OTSOBOL5	ABCB9_HUMAN	Increases Expression	[20]
Fructose-2,6-bisphosphatase TIGAR (TIGAR)	OTR7NMRJ	TIGAR_HUMAN	Increases Expression	[20]
Dual specificity protein phosphatase 22 (DUSP22)	OTEZ3U85	DUS22_HUMAN	Increases Expression	[20]
PAK4-inhibitor INKA2 (INKA2)	OT9RA64U	INKA2_HUMAN	Increases Expression	[20]
DNA damage-inducible transcript 4 protein (DDIT4)	OTHY8SY4	DDIT4_HUMAN	Increases Expression	[20]
LIM and cysteine-rich domains protein 1 (LMCD1)	OT3AWE8O	LMCD1_HUMAN	Decreases Expression	[20]
Signal-induced proliferation-associated 1-like protein 2 (SIPA1L2)	OT8NJE5D	SI1L2_HUMAN	Decreases Expression	[20]
Dolichol-phosphate mannosyltransferase subunit 3 (DPM3)	OTSB4XO0	DPM3_HUMAN	Increases Expression	[20]
DnaJ homolog subfamily B member 9 (DNAJB9)	OT38EQT6	DNJB9_HUMAN	Increases Expression	[20]
Mitochondrial fission process protein 1 (MTFP1)	OT3L6F7U	MTFP1_HUMAN	Increases Expression	[20]
SERTA domain-containing protein 1 (SERTAD1)	OTBHKZQP	SRTD1_HUMAN	Increases Expression	[20]
Oxidative stress-induced growth inhibitor 1 (OSGIN1)	OT9KIVZW	OSGI1_HUMAN	Decreases Expression	[20]
Heme transporter FLVCR2 (FLVCR2)	OTAM94ID	FLVC2_HUMAN	Decreases Expression	[20]
Exocyst complex component 7 (EXOC7)	OT4YA137	EXOC7_HUMAN	Increases Expression	[20]
5'-AMP-activated protein kinase subunit beta-1 (PRKAB1)	OT1OG4QZ	AAKB1_HUMAN	Affects Expression	[20]
Lysine-specific demethylase 3A (KDM3A)	OTZYJ8VN	KDM3A_HUMAN	Decreases Expression	[20]
RNA polymerase II subunit A C-terminal domain phosphatase (CTDP1)	OTHHFW17	CTDP1_HUMAN	Decreases Expression	[20]
Pleckstrin homology-like domain family A member 3 (PHLDA3)	OTXFUDO2	PHLA3_HUMAN	Increases Expression	[20]
Insulin-induced gene 2 protein (INSIG2)	OTX4VY51	INSI2_HUMAN	Increases Expression	[20]
Phosphoserine aminotransferase (PSAT1)	OTVV1YV9	SERC_HUMAN	Increases Expression	[20]
Sestrin-1 (SESN1)	OTSFDZWL	SESN1_HUMAN	Increases Expression	[20]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[35]
HLA class I histocompatibility antigen, B alpha chain (HLA-B)	OTNXFWY2	HLAB_HUMAN	Affects Expression	[36]
Osteocalcin (BGLAP)	OTK1YLWQ	OSTCN_HUMAN	Decreases Expression	[37]
HLA class I histocompatibility antigen, A alpha chain (HLA-A)	OTAH14LU	HLAA_HUMAN	Affects Expression	[36]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[35]
HLA class I histocompatibility antigen, alpha chain G (HLA-G)	OTMLK1KN	HLAG_HUMAN	Affects Expression	[36]
Glutathione peroxidase 3 (GPX3)	OT6PK94R	GPX3_HUMAN	Decreases Activity	[38]
Major histocompatibility complex class I-related gene protein (MR1)	OTZU3XX7	HMR1_HUMAN	Affects Expression	[36]
Elastin (ELN)	OTFSO7PG	ELN_HUMAN	Increases ADR	[12]
S-adenosylmethionine decarboxylase proenzyme (AMD1)	OTKAGZY3	DCAM_HUMAN	Increases ADR	[12]
Glutathione S-transferase P (GSTP1)	OTLP0A0Y	GSTP1_HUMAN	Increases Response To Substance	[39]
Ornithine decarboxylase (ODC1)	OTNDAGRR	DCOR_HUMAN	Increases ADR	[12]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Increases Response To Substance	[31]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adenocarcinoma	DC4IC79	NCIH23	Investigative	[1]
Adenocarcinoma	DCR1JC7	SW-620	Investigative	[1]
Adenocarcinoma	DCSIZSO	HCT116	Investigative	[1]
Chronic myelogenous leukemia	DC7ONVS	K-562	Investigative	[1]
Lung adenocarcinoma	DCGM5X2	EKVX	Investigative	[1]
Prostate carcinoma	DC5E5N0	PC-3	Investigative	[1]
Invasive ductal carcinoma	DCYH69N	HS 578T	Investigative	[40]

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] Letrozole 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: 5209).
• [4] Ifosfamide FDA Label
• [5] 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: 7201).
• [6] Aromatase inhibitors--theoretical concept and present experiences in the treatment of endometriosis. Zentralbl Gynakol. 2003 Jul-Aug;125(7-8):247-51.
• [7] Inhibition of drug metabolizing cytochrome P450s by the aromatase inhibitor drug letrozole and its major oxidative metabolite 4,4'-methanol-bisbenzonitrile in vitro. Cancer Chemother Pharmacol. 2009 Oct;64(5):867-75.
• [8] Double-blind, randomised, multicentre endocrine trial comparing two letrozole doses, in postmenopausal breast cancer patients. Eur J Cancer. 1999 Feb;35(2):208-13.
• [9] Letrozole concentration is associated with CYP2A6 variation but not with arthralgia in patients with breast cancer. Breast Cancer Res Treat. 2018 Nov;172(2):371-379.
• [10] Aromatase inhibition: translation into a successful therapeutic approach. Clin Cancer Res. 2005 Apr 15;11(8):2809-21. doi: 10.1158/1078-0432.CCR-04-2187.
• [11] Deactivation of anti-cancer drug letrozole to a carbinol metabolite by polymorphic cytochrome P450 2A6 in human liver microsomes. Xenobiotica. 2009 Nov;39(11):795-802. doi: 10.3109/00498250903171395.
• [12] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [13] Clomiphene citrate versus letrozole: molecular analysis of the endometrium in women with polycystic ovary syndrome. Fertil Steril. 2011 Oct;96(4):1051-6. doi: 10.1016/j.fertnstert.2011.07.1092.
• [14] Aromatase inhibition, testosterone, and seizures. Epilepsy Behav. 2004 Apr;5(2):260-3. doi: 10.1016/j.yebeh.2003.12.001.
• [15] Aromatase inhibitors: cellular and molecular effects. J Steroid Biochem Mol Biol. 2005 May;95(1-5):83-9. doi: 10.1016/j.jsbmb.2005.04.010.
• [16] Inhibition of estrogen receptor reduces connexin 43 expression in breast cancers. Toxicol Appl Pharmacol. 2018 Jan 1;338:182-190. doi: 10.1016/j.taap.2017.11.020. Epub 2017 Nov 24.
• [17] Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer. Clin Cancer Res. 2005 Jul 15;11(14):5319-28. doi: 10.1158/1078-0432.CCR-04-2402.
• [18] Synergistic activity of letrozole and sorafenib on breast cancer cells. Breast Cancer Res Treat. 2010 Nov;124(1):79-88. doi: 10.1007/s10549-009-0714-5. Epub 2010 Jan 7.
• [19] Comparison of lanosterol-14 alpha-demethylase (CYP51) of human and Candida albicans for inhibition by different antifungal azoles. Toxicology. 2006 Nov 10;228(1):24-32. doi: 10.1016/j.tox.2006.08.007. Epub 2006 Aug 12.
• [20] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [21] Pharmacokinetics and metabolism of ifosfamide in relation to DNA damage assessed by the COMET assay in children with cancer. Br J Cancer. 2005 May 9;92(9):1626-35.
• [22] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [23] Measurement of 4-hydroxylation of ifosfamide in human liver microsomes using the estimation of free and protein-bound acrolein and codetermination of keto- and carboxyifosfamide. J Cancer Res Clin Oncol. 2002 Jul;128(7):385-92.
• [24] Enhanced cyclophosphamide and ifosfamide activation in primary human hepatocyte cultures: response to cytochrome P-450 inducers and autoinduction by oxazaphosphorines. Cancer Res. 1997 May 15;57(10):1946-54.
• [25] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [26] Development of a substrate-activity based approach to identify the major human liver P-450 catalysts of cyclophosphamide and ifosfamide activation based on cDNA-expressed activities and liver microsomal P-450 profiles. Drug Metab Dispos. 1999 Jun;27(6):655-66.
• [27] CYP2C9 polymorphisms in human tumors. Anticancer Res. 2006 Jan-Feb;26(1A):299-305.
• [28] A novel distal enhancer module regulated by pregnane X receptor/constitutive androstane receptor is essential for the maximal induction of CYP2B6 gene expression. J Biol Chem. 2003 Apr 18;278(16):14146-52.
• [29] Identification of the polymorphically expressed CYP2C19 and the wild-type CYP2C9-ILE359 allele as low-Km catalysts of cyclophosphamide and ifosfamide activation. Pharmacogenetics. 1997 Jun;7(3):211-21.
• [30] Contribution of CYP3A5 to hepatic and renal ifosfamide N-dechloroethylation. Drug Metab Dispos. 2005 Jul;33(7):1074-81. doi: 10.1124/dmd.104.002279. Epub 2005 Apr 8.
• [31] Advantages of human hepatocyte-derived transformants expressing a series of human cytochrome p450 isoforms for genotoxicity examination. Toxicol Sci. 2010 Aug;116(2):488-97. doi: 10.1093/toxsci/kfq154. Epub 2010 May 27.
• [32] Retroviral transfer of human cytochrome P450 genes for oxazaphosphorine-based cancer gene therapy. Cancer Res. 1998 Oct 1;58(19):4391-401.
• [33] A prospective evaluation of ifosfamide-related nephrotoxicity in children and young adults. Cancer. 1995 Dec 15;76(12):2557-64. doi: 10.1002/1097-0142(19951215)76:12<2557::aid-cncr2820761223>3.0.co;2-9.
• [34] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [35] PXR-mediated induction of P-glycoprotein by anticancer drugs in a human colon adenocarcinoma-derived cell line. Cancer Chemother Pharmacol. 2010 Sep;66(4):765-71. doi: 10.1007/s00280-009-1221-4. Epub 2009 Dec 30.
• [36] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [37] Abnormalities in serum osteocalcin values in children receiving chemotherapy including ifosfamide. In Vivo. 1992 Mar-Apr;6(2):219-21.
• [38] Plasma glutathione peroxidase and its relationship to renal proximal tubule function. Mol Genet Metab. 1998 Nov;65(3):238-45. doi: 10.1006/mgme.1998.2760.
• [39] Role of GSTM1, GSTP1, and GSTT1 gene polymorphism in ifosfamide metabolism affecting neurotoxicity and nephrotoxicity in children. J Pediatr Hematol Oncol. 2005 Nov;27(11):582-9. doi: 10.1097/01.mph.0000187429.52616.8a.
• [40] Biologically active neutrophil chemokine pattern in tonsillitis.Clin Exp Immunol. 2004 Mar;135(3):511-8. doi: 10.1111/j.1365-2249.2003.02390.x.