Details of the Drug Combination

General Information of Drug Combination (ID: DCNZ2H5)

• Drug Combination Name: Maprotiline + Mebendazole
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Maprotiline (DMPWB7T): Small molecular drug
  Mebendazole (DMO14SG): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 4.5
  Bliss Independence Score: 4.5
  Loewe Additivity Score: 5.17
  LHighest Single Agent (HSA) Score: 5.17

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Maprotiline

Disease Entry	ICD 11	Status	REF
Depression	6A70-6A7Z	Approved	[2]
Major depressive disorder	6A70.3	Approved	[3]
Mixed anxiety and depressive disorder	N.A.	Investigative	[2]

Maprotiline Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Norepinephrine transporter (NET)	TTAWNKZ	SC6A2_HUMAN	Inhibitor	[6]

Maprotiline Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[7]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[7]

Maprotiline Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Increases ADR	[8]
Beclin-1 (BECN1)	OT4X293M	BECN1_HUMAN	Increases Expression	[9]

Indication(s) of Mebendazole

Disease Entry	ICD 11	Status	REF
Ascariasis	1F62	Approved	[4]
Enterobiasis	1F65	Approved	[4]
Helminth infection	1F90.0	Approved	[4]
Trichuris trichiura infection	1F6G	Approved	[4]
Worm infection	1F90.Z	Approved	[5]

Mebendazole Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Tubulin beta (TUBB)	TTYFKSZ	NOUNIPROTAC	Binder	[11]

Mebendazole Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[12]

Mebendazole Interacts with 43 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Increases Expression	[13]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases Expression	[14]
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Increases Expression	[15]
L-lactate dehydrogenase A chain (LDHA)	OTN7K4XB	LDHA_HUMAN	Decreases Expression	[16]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Increases Expression	[17]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[18]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases Expression	[19]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Increases Expression	[15]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Expression	[15]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[15]
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)	OTBPMIMW	G3P_HUMAN	Decreases Expression	[16]
Protein S100-A8 (S100A8)	OTVMOB3F	S10A8_HUMAN	Increases Expression	[20]
Protein S100-A9 (S100A9)	OTOARHCS	S10A9_HUMAN	Increases Expression	[20]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Expression	[21]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Expression	[15]
Interleukin-6 receptor subunit alpha (IL6R)	OTCQL07Z	IL6RA_HUMAN	Increases Expression	[10]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[19]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Increases Phosphorylation	[22]
Microtubule-associated protein tau (MAPT)	OTMTP2Z7	TAU_HUMAN	Decreases Expression	[23]
Solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1)	OTA675TJ	GTR1_HUMAN	Decreases Expression	[16]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[10]
Hexokinase-1 (HK1)	OTMPHE8O	HXK1_HUMAN	Decreases Expression	[16]
Bone morphogenetic protein 6 (BMP6)	OT9WN536	BMP6_HUMAN	Increases Expression	[15]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[19]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[19]
Multidrug resistance-associated protein 1 (ABCC1)	OTGUN89S	MRP1_HUMAN	Decreases Expression	[21]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Increases Expression	[15]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[16]
Mitogen-activated protein kinase 8 (MAPK8)	OTEREYS5	MK08_HUMAN	Increases Phosphorylation	[19]
Mitogen-activated protein kinase 9 (MAPK9)	OTCEVJ9E	MK09_HUMAN	Increases Phosphorylation	[19]
Neurogenic locus notch homolog protein 1 (NOTCH1)	OTI1WADQ	NOTC1_HUMAN	Decreases Expression	[24]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[16]
Transforming protein RhoA (RHOA)	OT6YOJ9N	RHOA_HUMAN	Decreases Expression	[25]
Ras-related C3 botulinum toxin substrate 1 (RAC1)	OTKRO61U	RAC1_HUMAN	Decreases Expression	[25]
Focal adhesion kinase 1 (PTK2)	OT3Q1JDY	FAK1_HUMAN	Decreases Expression	[25]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Increases Expression	[15]
Transcription factor HES-1 (HES1)	OT8P19W2	HES1_HUMAN	Decreases Expression	[24]
Advanced glycosylation end product-specific receptor (AGER)	OTPY0IH7	RAGE_HUMAN	Increases Expression	[20]
PTB-containing, cubilin and LRP1-interacting protein (PID1)	OT5YJ7FI	PCLI1_HUMAN	Increases Expression	[15]
Rho guanine nucleotide exchange factor 2 (ARHGEF2)	OTBQTFRT	ARHG2_HUMAN	Decreases Expression	[25]
Multidrug and toxin extrusion protein 1 (SLC47A1)	OTZX0U5Q	S47A1_HUMAN	Decreases Expression	[21]
NACHT, LRR and PYD domains-containing protein 3 (NLRP3)	OTZM6MHU	NLRP3_HUMAN	Increases Expression	[20]
Cystine/glutamate transporter (SLC7A11)	OTKJ6PXW	XCT_HUMAN	Increases Expression	[15]

References

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• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [4] Mebendazole FDA Label
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• [18] Mebendazole induces apoptosis via C-MYC inactivation in malignant ascites cell line (AGP01). Toxicol In Vitro. 2019 Oct;60:305-312. doi: 10.1016/j.tiv.2019.06.010. Epub 2019 Jun 14.
• [19] Stimulation of pro-inflammatory responses by mebendazole in human monocytic THP-1 cells through an ERK signaling pathway. Arch Toxicol. 2011 Mar;85(3):199-207. doi: 10.1007/s00204-010-0584-y. Epub 2010 Sep 17.
• [20] Development of a cell-based assay system considering drug metabolism and immune- and inflammatory-related factors for the risk assessment of drug-induced liver injury. Toxicol Lett. 2014 Jul 3;228(1):13-24. doi: 10.1016/j.toxlet.2014.04.005. Epub 2014 Apr 15.
• [21] Mebendazole, an antiparasitic drug, inhibits drug transporters expression in preclinical model of gastric peritoneal carcinomatosis. Toxicol In Vitro. 2017 Sep;43:87-91. doi: 10.1016/j.tiv.2017.06.007. Epub 2017 Jun 9.
• [22] Mebendazole induces apoptosis via Bcl-2 inactivation in chemoresistant melanoma cells. Mol Cancer Res. 2008 Aug;6(8):1308-15. doi: 10.1158/1541-7786.MCR-07-2159. Epub 2008 Jul 30.
• [23] Pharmacologic reductions of total tau levels; implications for the role of microtubule dynamics in regulating tau expression. Mol Neurodegener. 2006 Jul 26;1:6. doi: 10.1186/1750-1326-1-6.
• [24] Mebendazole is a potent inhibitor to chemoresistant T cell acute lymphoblastic leukemia cells. Toxicol Appl Pharmacol. 2020 Jun 1;396:115001. doi: 10.1016/j.taap.2020.115001. Epub 2020 Apr 8.
• [25] Flubendazole and mebendazole impair migration and epithelial to mesenchymal transition in oral cell lines. Chem Biol Interact. 2018 Sep 25;293:124-132. doi: 10.1016/j.cbi.2018.07.026. Epub 2018 Jul 31.