Details of the Drug Combination

General Information of Drug Combination (ID: DCMZYAN)

• Drug Combination Name: Mebendazole + Isoproterenol
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Mebendazole (DMO14SG): Small molecular drug
  Isoproterenol (DMK7MEY): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 22.11
  Bliss Independence Score: 22.11
  Loewe Additivity Score: 34.24
  LHighest Single Agent (HSA) Score: 34.24

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Mebendazole

Disease Entry	ICD 11	Status	REF
Ascariasis	1F62	Approved	[2]
Enterobiasis	1F65	Approved	[2]
Helminth infection	1F90.0	Approved	[2]
Trichuris trichiura infection	1F6G	Approved	[2]
Worm infection	1F90.Z	Approved	[3]

Mebendazole Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Tubulin beta (TUBB)	TTYFKSZ	NOUNIPROTAC	Binder	[8]

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	[9]

Mebendazole Interacts with 23 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Increases Expression	[10]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Increases Expression	[11]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[12]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[10]
Protein S100-A8 (S100A8)	OTVMOB3F	S10A8_HUMAN	Increases Expression	[13]
Protein S100-A9 (S100A9)	OTOARHCS	S10A9_HUMAN	Increases Expression	[13]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Expression	[14]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Expression	[10]
Interleukin-6 receptor subunit alpha (IL6R)	OTCQL07Z	IL6RA_HUMAN	Increases Expression	[7]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[15]
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	[7]
Hexokinase-1 (HK1)	OTMPHE8O	HXK1_HUMAN	Decreases Expression	[16]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[15]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[15]
Mitogen-activated protein kinase 8 (MAPK8)	OTEREYS5	MK08_HUMAN	Increases Phosphorylation	[15]
Mitogen-activated protein kinase 9 (MAPK9)	OTCEVJ9E	MK09_HUMAN	Increases Phosphorylation	[15]
Neurogenic locus notch homolog protein 1 (NOTCH1)	OTI1WADQ	NOTC1_HUMAN	Decreases Expression	[17]
Transcription factor HES-1 (HES1)	OT8P19W2	HES1_HUMAN	Decreases Expression	[17]
PTB-containing, cubilin and LRP1-interacting protein (PID1)	OT5YJ7FI	PCLI1_HUMAN	Increases Expression	[10]
Rho guanine nucleotide exchange factor 2 (ARHGEF2)	OTBQTFRT	ARHG2_HUMAN	Decreases Expression	[18]
Multidrug and toxin extrusion protein 1 (SLC47A1)	OTZX0U5Q	S47A1_HUMAN	Decreases Expression	[14]
NACHT, LRR and PYD domains-containing protein 3 (NLRP3)	OTZM6MHU	NLRP3_HUMAN	Increases Expression	[13]

Indication(s) of Isoproterenol

Disease Entry	ICD 11	Status	REF
Atrioventricular block	N.A.	Approved	[4]
Cardiac arrest	MC82	Approved	[4]
Common cold	CA00	Approved	[4]
Heart block	BC63	Approved	[5]
Melanoma	2C30	Phase 1	[6]

Isoproterenol Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adrenergic receptor beta-1 (ADRB1)	TTR6W5O	ADRB1_HUMAN	Agonist	[20]
Adrenergic receptor beta-2 (ADRB2)	TT2CJVK	ADRB2_HUMAN	Modulator	[20]
Interleukin-12 beta (IL12B)	TTGW72V	IL12B_HUMAN	Modulator	[21]

Isoproterenol Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Thiopurine methyltransferase (TPMT)	DEFQ8VO	TPMT_HUMAN	Metabolism	[22]

Isoproterenol Interacts with 40 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Apoptotic protease-activating factor 1 (APAF1)	OTJWIVY0	APAF_HUMAN	Increases Expression	[19]
ATP-binding cassette sub-family C member 3 (ABCC3)	OTC3IJV4	MRP3_HUMAN	Decreases Expression	[19]
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[19]
Metalloproteinase inhibitor 1 (TIMP1)	OTOXC51H	TIMP1_HUMAN	Decreases Expression	[19]
C-C motif chemokine 3 (CCL3)	OTW2H3ND	CCL3_HUMAN	Increases Expression	[19]
Heat shock cognate 71 kDa protein (HSPA8)	OTJI2RCI	HSP7C_HUMAN	Decreases Expression	[19]
Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A)	OT2D9DOV	TNR1A_HUMAN	Decreases Expression	[19]
Phosphatidylcholine translocator ABCB4 (ABCB4)	OTE6PY83	MDR3_HUMAN	Decreases Expression	[19]
14-3-3 protein sigma (SFN)	OTLJCZ1U	1433S_HUMAN	Decreases Expression	[19]
Heat shock 70 kDa protein 1-like (HSPA1L)	OTC2V1K6	HS71L_HUMAN	Decreases Expression	[19]
Metalloproteinase inhibitor 3 (TIMP3)	OTDGQAD1	TIMP3_HUMAN	Increases Expression	[19]
Heat shock-related 70 kDa protein 2 (HSPA2)	OTSDET7B	HSP72_HUMAN	Increases Expression	[19]
C-C motif chemokine 7 (CCL7)	OTDIS99H	CCL7_HUMAN	Decreases Expression	[19]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[19]
Four and a half LIM domains protein 1 (FHL1)	OTN535SU	FHL1_HUMAN	Decreases Expression	[19]
Phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1)	OTXEE550	APR_HUMAN	Increases Expression	[19]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Decreases Expression	[19]
Regenerating islet-derived protein 3-gamma (REG3G)	OTLIUY8Z	REG3G_HUMAN	Decreases Expression	[19]
Metalloproteinase inhibitor 4 (TIMP4)	OT8A68SW	TIMP4_HUMAN	Decreases Expression	[19]
Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2)	OTAQD3YV	ARNT2_HUMAN	Decreases Expression	[19]
Hypoxia-inducible factor 1-alpha inhibitor (HIF1AN)	OT5LIL3W	HIF1N_HUMAN	Decreases Expression	[19]
Hypoxia-inducible factor 3-alpha (HIF3A)	OTPWAAMC	HIF3A_HUMAN	Increases Expression	[19]
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Increases Expression	[10]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Activity	[23]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Expression	[24]
Natriuretic peptides A (NPPA)	OTMQNTNX	ANF_HUMAN	Increases Expression	[25]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[10]
Alkaline phosphatase, placental type (ALPP)	OTZU4G9W	PPB1_HUMAN	Increases Expression	[26]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Increases Expression	[27]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Decreases Expression	[28]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[10]
Beta-3 adrenergic receptor (ADRB3)	OTPMG4V7	ADRB3_HUMAN	Increases Activity	[29]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Increases Expression	[25]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[30]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[30]
Tumor necrosis factor-inducible gene 6 protein (TNFAIP6)	OT1SLUZH	TSG6_HUMAN	Decreases Expression	[10]
Ryanodine receptor 2 (RYR2)	OT0PF19E	RYR2_HUMAN	Increases Phosphorylation	[31]
Guanine nucleotide-binding protein G(olf) subunit alpha (GNAL)	OTESDTEU	GNAL_HUMAN	Increases Response To Substance	[32]
Neuroendocrine secretory protein 55 (GNAS)	OTMH8BKJ	GNAS3_HUMAN	Increases Response To Substance	[32]
Interleukin-5 receptor subunit alpha (IL5RA)	OTMSLUG9	IL5RA_HUMAN	Affects Response To Substance	[33]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] Mebendazole FDA Label
• [3] Emerging drugs for irritable bowel syndrome. Expert Opin Emerg Drugs. 2006 May;11(2):293-313.
• [4] Isoproterenol FDA Label
• [5] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 083346.
• [6] A phase 1 study of AS1409, a novel antibody-cytokine fusion protein, in patients with malignant melanoma or renal cell carcinoma. Clin Cancer Res. 2011 Apr 1;17(7):1998-2005.
• [7] Cell-based and cytokine-directed chemical screen to identify potential anti-multiple myeloma agents. Leuk Res. 2010 Jul;34(7):917-24. doi: 10.1016/j.leukres.2009.12.002. Epub 2010 Feb 8.
• [8] Flubendazole interferes with a wide spectrum of cell homeostatic mechanisms in Echinococcus granulosus protoscoleces. Parasitol Int. 2009 Sep;58(3):270-7.
• [9] Alveolar echinococcosis of the liver in an adult with human immunodeficiency virus type-1 infection. Infection. 2004 Oct;32(5):299-302.
• [10] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [11] Selection of drugs to test the specificity of the Tg.AC assay by screening for induction of the gadd153 promoter in vitro. Toxicol Sci. 2003 Aug;74(2):260-70. doi: 10.1093/toxsci/kfg113. Epub 2003 May 2.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Mebendazole targets essential proteins in glucose metabolism leading gastric cancer cells to death. Toxicol Appl Pharmacol. 2023 Sep 15;475:116630. doi: 10.1016/j.taap.2023.116630. Epub 2023 Jul 18.
• [17] 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.
• [18] 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.
• [19] Isoproterenol effects evaluated in heart slices of human and rat in comparison to rat heart in vivo. Toxicol Appl Pharmacol. 2014 Jan 15;274(2):302-12.
• [20] Current therapeutic uses and potential of beta-adrenoceptor agonists and antagonists. Eur J Clin Pharmacol. 1998 Feb;53(6):389-404.
• [21] A phase 1 study of AS1409, a novel antibody-cytokine fusion protein, in patients with malignant melanoma or renal cell carcinoma. Clin Cancer Res. 2011 Apr 1;17(7):1998-2005.
• [22] Identification, characterization, and ontogenic study of a catechol O-methyltransferase from zebrafish. Aquat Toxicol. 2011 Mar;102(1-2):18-23.
• [23] Hypokalemia from beta2-receptor stimulation by circulating epinephrine. N Engl J Med. 1983 Dec 8;309(23):1414-9. doi: 10.1056/NEJM198312083092303.
• [24] The regulation of human vascular smooth muscle extracellular matrix protein production by alpha- and beta-adrenoceptor stimulation. J Hypertens. 2002 Feb;20(2):287-94. doi: 10.1097/00004872-200202000-00019.
• [25] Low doses of BPF-induced hypertrophy in cardiomyocytes derived from human embryonic stem cells via disrupting the mitochondrial fission upon the interaction between ER and calcineurin A-DRP1 signaling pathway. Cell Biol Toxicol. 2022 Jun;38(3):409-426. doi: 10.1007/s10565-021-09615-y. Epub 2021 May 22.
• [26] The effects of desmethylimipramine on cyclic AMP-stimulated gene transcription in a model cell system. Biochem Pharmacol. 2005 Sep 1;70(5):762-9. doi: 10.1016/j.bcp.2005.06.012.
• [27] Isoproterenol inhibits angiotensin II-stimulated proliferation and reactive oxygen species production in vascular smooth muscle cells through heme oxygenase-1. Biol Pharm Bull. 2009 Jun;32(6):1047-52. doi: 10.1248/bpb.32.1047.
• [28] Impaired PARP activity in response to the -adrenergic receptor agonist isoproterenol. Toxicol In Vitro. 2018 Aug;50:29-39. doi: 10.1016/j.tiv.2018.02.001. Epub 2018 Feb 10.
• [29] Discovery of a novel series of biphenyl benzoic acid derivatives as highly potent and selective human beta3 adrenergic receptor agonists with good oral bioavailability. Part II. J Med Chem. 2008 Jul 10;51(13):4002-20. doi: 10.1021/jm8000345. Epub 2008 Jun 14.
• [30] A unique mechanism of beta-blocker action: carvedilol stimulates beta-arrestin signaling. Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16657-62. doi: 10.1073/pnas.0707936104. Epub 2007 Oct 9.
• [31] Carvedilol and its new analogs suppress arrhythmogenic store overload-induced Ca2+ release. Nat Med. 2011 Jul 10;17(8):1003-9. doi: 10.1038/nm.2406.
• [32] Identification of specific ligands for orphan olfactory receptors. G protein-dependent agonism and antagonism of odorants. J Biol Chem. 2005 Mar 25;280(12):11807-15. doi: 10.1074/jbc.M411508200. Epub 2004 Dec 14.
• [33] Autocrine interaction between IL-5 and IL-1beta mediates altered responsiveness of atopic asthmatic sensitized airway smooth muscle. J Clin Invest. 1999 Sep;104(5):657-67. doi: 10.1172/JCI7137.