Details of the Drug Combination

General Information of Drug Combination (ID: DCQ24P0)

• Drug Combination Name: Artesunate + Quinine
• Indication: Malaria; Status: Phase 4 [1]
• Component Drugs:
  Artesunate (DMR27C8): Small molecular drug
  Quinine (DMSWYF5): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Artesunate

Disease Entry	ICD 11	Status	REF
Infection of P. falciparum	1F40	Approved	[2]
Malaria	1F40-1F45	Approved	[3]
Plasmodium falciparum malaria	1F40	Approved	[2]

Artesunate Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Sarcoplasmic/endoplasmic reticulum calcium ATPase (ATP2A)	TTZVSJ2	NOUNIPROTAC	Inhibitor	[3]

Artesunate Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[8]

Artesunate Interacts with 57 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Catalase (CAT)	OTHEBX9R	CATA_HUMAN	Increases Expression	[5]
Transcription factor Sp1 (SP1)	OTISPT4X	SP1_HUMAN	Decreases Expression	[5]
Glutathione S-transferase P (GSTP1)	OTLP0A0Y	GSTP1_HUMAN	Decreases Expression	[5]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[5]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[5]
Serine/threonine-protein kinase Chk1 (CHEK1)	OTTTI622	CHK1_HUMAN	Increases Phosphorylation	[9]
Ubiquitin-like protein ATG12 (ATG12)	OTJRO09Y	ATG12_HUMAN	Increases Expression	[10]
Apoptosis-inducing factor 1, mitochondrial (AIFM1)	OTKPWB7Q	AIFM1_HUMAN	Affects Localization	[11]
Serine/threonine-protein kinase Chk2 (CHEK2)	OT8ZPCNS	CHK2_HUMAN	Increases Phosphorylation	[9]
Metalloproteinase inhibitor 1 (TIMP1)	OTOXC51H	TIMP1_HUMAN	Increases Expression	[10]
Fibronectin (FN1)	OTB5ZN4Q	FINC_HUMAN	Decreases Expression	[10]
Ferritin heavy chain (FTH1)	OT6IFS0O	FRIH_HUMAN	Decreases Expression	[10]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[12]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[11]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[11]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Decreases Expression	[10]
Replication protein A 32 kDa subunit (RPA2)	OTZ54WAF	RFA2_HUMAN	Increases Phosphorylation	[9]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Phosphorylation	[9]
Desmin (DES)	OTI09KBW	DESM_HUMAN	Decreases Expression	[10]
Phospholipid hydroperoxide glutathione peroxidase GPX4 (GPX4)	OTRAFFX2	GPX4_HUMAN	Decreases Activity	[10]
Serine/threonine-protein kinase mTOR (MTOR)	OTHH8KU7	MTOR_HUMAN	Decreases Phosphorylation	[6]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Affects Expression	[11]
Actin, aortic smooth muscle (ACTA2)	OTEDLG8E	ACTA_HUMAN	Decreases Expression	[10]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[11]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Decreases Expression	[10]
Nuclear receptor coactivator 4 (NCOA4)	OTRVU0UA	NCOA4_HUMAN	Decreases Expression	[10]
Nuclear factor erythroid 2-related factor 2 (NFE2L2)	OT0HENJ5	NF2L2_HUMAN	Affects Localization	[13]
Microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B)	OTUYHB84	MLP3B_HUMAN	Increases Lipidation	[6]
Autophagy protein 5 (ATG5)	OT4T5SMS	ATG5_HUMAN	Increases Expression	[10]
DNA dC->dU-editing enzyme APOBEC-3C (APOBEC3C)	OTPL0AI1	ABC3C_HUMAN	Increases Expression	[9]
Ubiquitin-like-conjugating enzyme ATG3 (ATG3)	OT28VBVK	ATG3_HUMAN	Increases Expression	[10]
Small ribosomal subunit protein uS8 (RPS15A)	OT0BUA12	RS15A_HUMAN	Decreases Response To Substance	[7]
Mitochondrial thiamine pyrophosphate carrier (SLC25A19)	OT157TY3	TPC_HUMAN	Decreases Response To Substance	[7]
Atypical kinase COQ8A, mitochondrial (COQ8A)	OT1ETSA2	COQ8A_HUMAN	Decreases Response To Substance	[7]
Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial (MTHFD2)	OT1LQSGX	MTDC_HUMAN	Decreases Response To Substance	[7]
Large ribosomal subunit protein uL30 (RPL7)	OT4WCQBE	RL7_HUMAN	Decreases Response To Substance	[7]
Glutamate--cysteine ligase regulatory subunit (GCLM)	OT6CP234	GSH0_HUMAN	Decreases Response To Substance	[14]
Integrin beta-1 (ITGB1)	OT6G1IAR	ITB1_HUMAN	Increases Response To Substance	[7]
CAP-Gly domain-containing linker protein 4 (CLIP4)	OT75KVQK	CLIP4_HUMAN	Increases Response To Substance	[7]
Glutathione S-transferase theta-2 (GSTT2)	OTANW3TJ	GST2_HUMAN	Affects Response To Substance	[14]
ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 2 (BST1)	OTAV5SE7	BST1_HUMAN	Increases Response To Substance	[7]
Small ribosomal subunit protein eS12 (RPS12)	OTBRQ8MS	RS12_HUMAN	Decreases Response To Substance	[7]
Dopamine beta-hydroxylase (DBH)	OTC6I2SP	DOPO_HUMAN	Increases Response To Substance	[7]
Glutamate--cysteine ligase catalytic subunit (GCLC)	OTESDI4D	GSH1_HUMAN	Decreases Response To Substance	[14]
Nck-associated protein 1 (NCKAP1)	OTEZQXXJ	NCKP1_HUMAN	Increases Response To Substance	[7]
Small ribosomal subunit protein eS32 (RPL41)	OTFW5IFO	RS32_HUMAN	Decreases Response To Substance	[7]
Translationally-controlled tumor protein (TPT1)	OTHMTRJU	TCTP_HUMAN	Affects Response To Substance	[15]
Nascent polypeptide-associated complex subunit alpha (NACA)	OTLP1KR3	NACA_HUMAN	Decreases Response To Substance	[7]
Glutathione S-transferase Mu 4 (GSTM4)	OTOTF8DU	GSTM4_HUMAN	Affects Response To Substance	[14]
Maleylacetoacetate isomerase (GSTZ1)	OTQ43JCE	MAAI_HUMAN	Affects Response To Substance	[14]
Large ribosomal subunit protein eL6 (RPL6)	OTRU71O4	RL6_HUMAN	Decreases Response To Substance	[7]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Response To Substance	[7]
Frizzled-7 (FZD7)	OTTK3F6E	FZD7_HUMAN	Increases Response To Substance	[7]
Serine/arginine-rich splicing factor 2 (SRSF2)	OTVDHO6U	SRSF2_HUMAN	Decreases Response To Substance	[7]
T-complex protein 1 subunit beta (CCT2)	OTW1VV4E	TCPB_HUMAN	Decreases Response To Substance	[7]
Glutathione S-transferase 3, mitochondrial (MGST3)	OTYK80JA	MGST3_HUMAN	Affects Response To Substance	[14]
Filamin-A (FLNA)	OTYZ9JXM	FLNA_HUMAN	Increases Response To Substance	[7]

Indication(s) of Quinine

Disease Entry	ICD 11	Status	REF
Malaria	1F40-1F45	Approved	[4]

Quinine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
E3 ubiquitin-protein ligase COP1 (RFWD2)	TT05DLS	COP1_HUMAN	Modulator	[16]

Quinine Interacts with 6 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[17]
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[18]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[19]
Organic cation/carnitine transporter 2 (SLC22A5)	DT3HUVD	S22A5_HUMAN	Substrate	[20]
Organic cation/carnitine transporter 1 (SLC22A4)	DT2EG60	S22A4_HUMAN	Substrate	[21]
Na(+)/Cl(-) betaine/GABA transporter (SLC6A12)	DTBPTJF	S6A12_HUMAN	Substrate	[22]

Quinine Interacts with 8 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[23]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[24]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[25]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[26]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[26]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[27]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[28]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[29]

Quinine Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Activity	[30]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Decreases Activity	[30]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Activity	[30]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases Expression	[31]
Solute carrier family 22 member 2 (SLC22A2)	OTGFK1AL	S22A2_HUMAN	Decreases Activity	[32]
Solute carrier family 22 member 1 (SLC22A1)	OT7817I4	S22A1_HUMAN	Decreases Activity	[32]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Affects Uptake	[33]
Glutathione S-transferase P (GSTP1)	OTLP0A0Y	GSTP1_HUMAN	Decreases Activity	[34]
Glutathione S-transferase Mu 1 (GSTM1)	OTSBF2MO	GSTM1_HUMAN	Decreases Activity	[34]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Increases Expression	[31]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[35]
Sodium/hydrogen exchanger 7 (SLC9A7)	OTVDLTYA	SL9A7_HUMAN	Decreases Activity	[36]
Solute carrier organic anion transporter family member 1A2 (SLCO1A2)	OTO70C5O	SO1A2_HUMAN	Increases Uptake	[37]

References

• [1] ClinicalTrials.gov (NCT01805232) Intravenous Artesunate and Malaria
• [2] Artesunate FDA Label
• [3] The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs. Curr Med Chem. 2008;15(2):161-71.
• [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: 2510).
• [5] Combination treatment of malignant B cells using the anti-CD20 antibody rituximab and the anti-malarial artesunate. Int J Oncol. 2009 Jul;35(1):149-58.
• [6] Artesunate induces autophagy dependent apoptosis through upregulating ROS and activating AMPK-mTOR-ULK1 axis in human bladder cancer cells. Chem Biol Interact. 2020 Nov 1;331:109273. doi: 10.1016/j.cbi.2020.109273. Epub 2020 Sep 28.
• [7] Factors determining sensitivity or resistance of tumor cell lines towards artesunate. Chem Biol Interact. 2010 Apr 15;185(1):42-52.
• [8] Identification of human cytochrome P(450)s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data. Eur J Clin Pharmacol. 2003 Sep;59(5-6):429-42.
• [9] Induction of APOBEC3C Facilitates the Genotoxic Stress-Mediated Cytotoxicity of Artesunate. Chem Res Toxicol. 2019 Dec 16;32(12):2526-2537. doi: 10.1021/acs.chemrestox.9b00358. Epub 2019 Nov 11.
• [10] Artesunate alleviates liver fibrosis by regulating ferroptosis signaling pathway. Biomed Pharmacother. 2019 Jan;109:2043-2053. doi: 10.1016/j.biopha.2018.11.030. Epub 2018 Nov 26.
• [11] Artesunate induces apoptosis through caspase-dependent and -independent mitochondrial pathways in human myelodysplastic syndrome SKM-1 cells. Chem Biol Interact. 2014 Aug 5;219:28-36. doi: 10.1016/j.cbi.2014.03.011. Epub 2014 Apr 3.
• [12] AMG900 as novel inhibitor of the translationally controlled tumor protein. Chem Biol Interact. 2021 Jan 25;334:109349. doi: 10.1016/j.cbi.2020.109349. Epub 2020 Nov 28.
• [13] Untargeted Proteomics and Systems-Based Mechanistic Investigation of Artesunate in Human Bronchial Epithelial Cells. Chem Res Toxicol. 2015 Oct 19;28(10):1903-13. doi: 10.1021/acs.chemrestox.5b00105. Epub 2015 Sep 21.
• [14] Glutathione-related enzymes contribute to resistance of tumor cells and low toxicity in normal organs to artesunate. In Vivo. 2005 Jan-Feb;19(1):225-32.
• [15] Mechanistic perspectives for 1,2,4-trioxanes in anti-cancer therapy. Drug Resist Updat. 2005 Feb-Apr;8(1-2):85-97. doi: 10.1016/j.drup.2005.04.003.
• [16] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [17] Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
• [18] Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol. 1997 Jul;16(7):871-81.
• [19] Comparison of type I and type II organic cation transport by organic cation transporters and organic anion-transporting polypeptides. J Pharmacol Exp Ther. 2001 Jul;298(1):110-5.
• [20] Na(+)-dependent carnitine transport by organic cation transporter (OCTN2): its pharmacological and toxicological relevance. J Pharmacol Exp Ther. 1999 Nov;291(2):778-84.
• [21] Novel membrane transporter OCTN1 mediates multispecific, bidirectional, and pH-dependent transport of organic cations. J Pharmacol Exp Ther. 1999 May;289(2):768-73.
• [22] The Transporter Classification Database (TCDB): recent advances. Nucleic Acids Res. 2016 Jan 4;44(D1):D372-9. (ID: 2.A.22.3.1)
• [23] Quinine induced simvastatin toxicity through cytochrome inhibition - a case report. BMC Geriatr. 2016 Oct 1;16(1):168.
• [24] The roles of cytochrome P450 3A4 and 1A2 in the 3-hydroxylation of quinine in vivo. Clin Pharmacol Ther. 1999 Nov;66(5):454-60.
• [25] Inhibition of cytochrome P450 2D6: structure-activity studies using a series of quinidine and quinine analogues. Chem Res Toxicol. 2003 Apr;16(4):450-9.
• [26] Drug Interactions Flockhart Table
• [27] Role of cytochrome P450 2C8 in drug metabolism and interactions. Pharmacol Rev. 2016 Jan;68(1):168-241.
• [28] Identification of human cytochrome P450 isoforms involved in the 3-hydroxylation of quinine by human live microsomes and nine recombinant human cytochromes P450. J Pharmacol Exp Ther. 1996 Dec;279(3):1327-34.
• [29] Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology. 2001 Feb;120(2):525-33.
• [30] Application of higher throughput screening (HTS) inhibition assays to evaluate the interaction of antiparasitic drugs with cytochrome P450s. Drug Metab Dispos. 2001 Jan;29(1):30-5.
• [31] Cytochrome P450 1A1/2 induction by antiparasitic drugs: dose-dependent increase in ethoxyresorufin O-deethylase activity and mRNA caused by quinine, primaquine and albendazole in HepG2 cells. Eur J Clin Pharmacol. 2002 Nov;58(8):537-42.
• [32] Involvement of aryl hydrocarbon receptor in the cytotoxicity of corannulene and its derivatives. Toxicol Lett. 2020 Mar 15;321:114-121. doi: 10.1016/j.toxlet.2019.12.012. Epub 2019 Dec 9.
• [33] Stereoselective transport of hydrophilic quaternary drugs by human MDR1 and rat Mdr1b P-glycoproteins. Br J Pharmacol. 2002 Apr;135(7):1685-94. doi: 10.1038/sj.bjp.0704620.
• [34] Inhibition of glutathione S-transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance. Int J Cancer. 2002 Feb 10;97(5):700-5.
• [35] Voltage-dependent profile of human ether-a-go-go-related gene channel block is influenced by a single residue in the S6 transmembrane domain. Mol Pharmacol. 2003 May;63(5):1051-8. doi: 10.1124/mol.63.5.1051.
• [36] Molecular cloning and characterization of a novel (Na+,K+)/H+ exchanger localized to the trans-Golgi network. J Biol Chem. 2001 May 18;276(20):17387-94. doi: 10.1074/jbc.M101319200. Epub 2001 Feb 26.
• [37] Expression of Organic Anion Transporting Polypeptide 1A2 in Red Blood Cells and Its Potential Impact on Antimalarial Therapy. Drug Metab Dispos. 2016 Oct;44(10):1562-8. doi: 10.1124/dmd.116.069807. Epub 2016 Aug 8.