Details of the Drug Combination

General Information of Drug Combination (ID: DCXRDE4)

• Drug Combination Name: Methylene blue + Hydroxychloroquine
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Methylene blue (DMJAPE7): N.A.
  Hydroxychloroquine (DMSIVND): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 0.87
  Bliss Independence Score: 0.87
  Loewe Additivity Score: 1.45
  LHighest Single Agent (HSA) Score: 1.45

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Methylene blue

Disease Entry	ICD 11	Status	REF
Acquired methemoglobinemia	3A93	Approved	[2]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[3]

Methylene blue Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Monoamine oxidase (MAO)	TT32XQJ	NOUNIPROTAC	.	[7]
Guanylate cyclase (GC)	TT6HPVC	NOUNIPROTAC	Inhibitor	[8]

Methylene blue Interacts with 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Amine oxidase B (MAOB)	OTTDFM1O	AOFB_HUMAN	Decreases Activity	[9]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Affects Activity	[10]
Microtubule-associated protein tau (MAPT)	OTMTP2Z7	TAU_HUMAN	Increases Expression	[11]
Glucose-6-phosphate 1-dehydrogenase (G6PD)	OT300SMK	G6PD_HUMAN	Increases Activity	[12]
Acetylcholinesterase (ACHE)	OT2H8HG6	ACES_HUMAN	Decreases Activity	[13]
6-phosphogluconate dehydrogenase, decarboxylating (PGD)	OTVG296F	6PGD_HUMAN	Increases Activity	[12]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases ADR	[14]

Indication(s) of Hydroxychloroquine

Disease Entry	ICD 11	Status	REF
Chronic renal failure	GB61.Z	Approved	[4]
Malaria	1F40-1F45	Approved	[5]
Plasmodium falciparum malaria	1F40	Approved	[4]
Plasmodium malariae malaria	N.A.	Approved	[4]
Plasmodium ovale malaria	N.A.	Approved	[4]
Systemic lupus erythematosus	4A40.0	Approved	[4]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[6]
Colon cancer	2B90.Z	Investigative	[4]

Hydroxychloroquine Interacts with 4 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
HUMAN pH-dependent viral fusion/replication (pH-DVF/R)	TTD16BI	N.A.	Inhibitor	[15]
HUMAN glycosylation of host receptor (GHR)	TTZGK1R	N.A.	Inhibitor	[15]
Toll-like receptor 7 (TLR7)	TTRJ1K4	TLR7_HUMAN	Antagonist	[16]
HUMAN toll-like receptor 7/9 signalling pathway (TLR7/9 pathway)	TT3A1EZ	N.A.	Inhibitor	[17]

Hydroxychloroquine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[18]

Hydroxychloroquine Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[19]

Hydroxychloroquine Interacts with 30 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Decreases Activity	[20]
Interferon-induced protein with tetratricopeptide repeats 3 (IFIT3)	OTPGHZB9	IFIT3_HUMAN	Increases Expression	[21]
CASP8 and FADD-like apoptosis regulator (CFLAR)	OTX14BAS	CFLAR_HUMAN	Decreases Expression	[22]
Serine/threonine-protein kinase/endoribonuclease IRE1 (ERN1)	OTY9R6FZ	ERN1_HUMAN	Increases Expression	[21]
Nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1)	OT4TMERS	NFAC1_HUMAN	Affects Expression	[23]
Claudin-1 (CLDN1)	OT27KV99	CLD1_HUMAN	Increases Expression	[24]
Interferon beta (IFNB1)	OTYQGUB5	IFNB_HUMAN	Increases Expression	[21]
C-X-C motif chemokine 10 (CXCL10)	OTTLQ6S0	CXL10_HUMAN	Increases Expression	[21]
3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)	OTRT3F3U	HMDH_HUMAN	Affects Expression	[25]
Alkaline phosphatase, tissue-nonspecific isozyme (ALPL)	OTG7J4BP	PPBT_HUMAN	Affects Expression	[25]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases Phosphorylation	[21]
Cathepsin B (CTSB)	OTP9G5QB	CATB_HUMAN	Affects Localization	[26]
72 kDa type IV collagenase (MMP2)	OT5NIWA2	MMP2_HUMAN	Decreases Expression	[27]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[28]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[28]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Increases Degradation	[21]
CD40 ligand (CD40LG)	OT75Z6A6	CD40L_HUMAN	Decreases Expression	[23]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[22]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Increases Expression	[21]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Activity	[26]
TNF receptor-associated factor 3 (TRAF3)	OT5TQBGV	TRAF3_HUMAN	Increases Expression	[21]
Nuclear factor of activated T-cells, cytoplasmic 2 (NFATC2)	OTK5T6HZ	NFAC2_HUMAN	Affects Localization	[23]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Increases Expression	[29]
Interferon regulatory factor 3 (IRF3)	OT81U8ME	IRF3_HUMAN	Increases Phosphorylation	[21]
Occludin (OCLN)	OTSUTVWL	OCLN_HUMAN	Increases Expression	[24]
Mitochondrial antiviral-signaling protein (MAVS)	OTTQ0J64	MAVS_HUMAN	Increases Expression	[21]
S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2)	OTCA9WCM	RSAD2_HUMAN	Increases Expression	[21]
Interferon-induced helicase C domain-containing protein 1 (IFIH1)	OTZA2AHA	IFIH1_HUMAN	Increases Expression	[21]
Toll-like receptor 9 (TLR9)	OTFZ45HX	TLR9_HUMAN	Decreases Expression	[30]
7-dehydrocholesterol reductase (DHCR7)	OTLILBUI	DHCR7_HUMAN	Affects Expression	[25]

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] Recombinant Plasmodium falciparum glutathione reductase is inhibited by the antimalarial dye methylene blue. FEBS Lett. 1998 Feb 6;422(3):311-4.
• [3] ClinicalTrials.gov (NCT04370288) Clinical Application of Methylene Blue for Treatment of Covid-19 Patients. U.S. National Institutes of Health.
• [4] Hydroxychloroquine 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: 7198).
• [6] ClinicalTrials.gov (NCT04341727) Hydroxychloroquine,Hydroxychloroquine,Azithromycin in the Treatment of SARS CoV-2 Infection (WU352). U.S. National Institutes of Health.
• [7] Photoluminescence of CdTe nanocrystals modulated by methylene blue and DNA. A label-free luminescent signaling nanohybrid platform. Phys Chem Chem Phys. 2009 Jul 7;11(25):5062-9.
• [8] Curcumin ameliorates high glucose-induced acute vascular endothelial dysfunction in rat thoracic aorta. Clin Exp Pharmacol Physiol. 2009 Dec;36(12):1177-82.
• [9] Inhibition of the bioactivation of the neurotoxin MPTP by antioxidants, redox agents and monoamine oxidase inhibitors. Food Chem Toxicol. 2011 Aug;49(8):1773-81.
• [10] Identification of environmental chemicals that activate p53 signaling after in vitro metabolic activation. Arch Toxicol. 2022 Jul;96(7):1975-1987. doi: 10.1007/s00204-022-03291-5. Epub 2022 Apr 18.
• [11] 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.
• [12] Defenses against oxidation in human erythrocytes: role of glutathione reductase in the activation of glucose decarboxylation by hemolytic drugs. J Lab Clin Med. 1991 Apr;117(4):325-31.
• [13] Profiling the Tox21 Chemical Collection for Acetylcholinesterase Inhibition. Environ Health Perspect. 2021 Apr;129(4):47008. doi: 10.1289/EHP6993. Epub 2021 Apr 12.
• [14] 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.
• [15] Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020 Mar;30(3):269-271.
• [16] TLR7/9 antagonists as therapeutics for immune-mediated inflammatory disorders. Inflamm Allergy Drug Targets. 2007 Dec;6(4):223-35.
• [17] Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol. 2020 Mar;16(3):155-166.
• [18] MDR-ABC transporters: biomarkers in rheumatoid arthritis. Clin Exp Rheumatol. 2013 Sep-Oct;31(5):779-87.
• [19] Hydroxychloroquine: a physiologically-based pharmacokinetic model in the context of cancer-related autophagy modulation. J Pharmacol Exp Ther. 2018 Jun;365(3):447-459.
• [20] Somer M, Kallio J, Pesonen U, Pyykko K, Huupponen R, Scheinin M "Influence of hydroxychloroquine on the bioavailability of oral metoprolol." Br J Clin Pharmacol 49 (2000): 549-54. [PMID: 10848718]
• [21] Hydroxychloroquine-inhibited dengue virus is associated with host defense machinery. J Interferon Cytokine Res. 2015 Mar;35(3):143-56. doi: 10.1089/jir.2014.0038. Epub 2014 Oct 16.
• [22] Hydroxychloroquine potentiates Fas-mediated apoptosis of rheumatoid synoviocytes. Clin Exp Immunol. 2006 Jun;144(3):503-11. doi: 10.1111/j.1365-2249.2006.03070.x.
• [23] Hydroxychloroquine inhibits CD154 expression in CD4(+) T lymphocytes of systemic lupus erythematosus through NFAT, but not STAT5, signaling. Arthritis Res Ther. 2017 Aug 9;19(1):183. doi: 10.1186/s13075-017-1393-y.
• [24] Chloroquine and Hydroxychloroquine Increase Retinal Pigment Epithelial Layer Permeability. J Biochem Mol Toxicol. 2015 Jul;29(7):299-304. doi: 10.1002/jbt.21696. Epub 2015 Mar 9.
• [25] Hydroxychloroquine decreases human MSC-derived osteoblast differentiation and mineralization in vitro. J Cell Mol Med. 2018 Feb;22(2):873-882. doi: 10.1111/jcmm.13373. Epub 2017 Oct 3.
• [26] Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine. Oncogene. 2003 Jun 19;22(25):3927-36. doi: 10.1038/sj.onc.1206622.
• [27] Attenuation of chloroquine and hydroxychloroquine on the invasive potential of bladder cancer through targeting matrix metalloproteinase 2 expression. Environ Toxicol. 2021 Nov;36(11):2138-2145. doi: 10.1002/tox.23328. Epub 2021 Jul 19.
• [28] Reactive oxygen species mediate chloroquine-induced expression of chemokines by human astroglial cells. Glia. 2004 Jul;47(1):9-20. doi: 10.1002/glia.20017.
• [29] d-galactose induces premature senescence of lens epithelial cells by disturbing autophagy flux and mitochondrial functions. Toxicol Lett. 2018 Jun 1;289:99-106. doi: 10.1016/j.toxlet.2018.02.001. Epub 2018 Feb 6.
• [30] Antagonist-mediated down-regulation of Toll-like receptors increases the prevalence of human papillomavirus infection in systemic lupus erythematosus. Arthritis Res Ther. 2012 Apr 18;14(2):R80. doi: 10.1186/ar3803.