Details of the Drug Combination

General Information of Drug Combination (ID: DCP0YM1)

• Drug Combination Name: Piperaquine + Tetrandrine
• Indication: Hepatoblastoma; Status: Investigative [1]
• Component Drugs:
  Piperaquine (DMT70RC): Small molecular drug
  Tetrandrine (DMAOJBX): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: HB3
  Zero Interaction Potency (ZIP) Score: 10.23
  Bliss Independence Score: 10.768
  Loewe Additivity Score: 4.272
  LHighest Single Agent (HSA) Score: 8.066

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Piperaquine

Disease Entry	ICD 11	Status	REF
Malaria	1F40-1F45	Approved	[2]

Piperaquine 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	[2]

Piperaquine Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[5]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[6]

Indication(s) of Tetrandrine

Disease Entry	ICD 11	Status	REF
Sarcoma	2A60-2C35	Phase 1	[3]
Colorectal cancer	2B91.Z	Discontinued in Phase 3	[4]

Tetrandrine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Calcium channel unspecific (CaC)	TT5HONZ	NOUNIPROTAC	Antagonist	[8]

Tetrandrine Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[9]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[10]

Tetrandrine Interacts with 51 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Glutathionylation	[11]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Increases Glutathionylation	[11]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[12]
Ubiquitin-like protein ATG12 (ATG12)	OTJRO09Y	ATG12_HUMAN	Increases Expression	[13]
Ubiquitin-like modifier-activating enzyme ATG7 (ATG7)	OTVT4YA1	ATG7_HUMAN	Decreases Expression	[7]
Apoptosis-inducing factor 1, mitochondrial (AIFM1)	OTKPWB7Q	AIFM1_HUMAN	Increases Expression	[13]
Zinc finger protein SNAI1 (SNAI1)	OTDPYAMC	SNAI1_HUMAN	Decreases Expression	[14]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Decreases Phosphorylation	[14]
Collagen alpha-1(I) chain (COL1A1)	OTI31178	CO1A1_HUMAN	Decreases Expression	[15]
Prelamin-A/C (LMNA)	OT3SG7ZR	LMNA_HUMAN	Increases Expression	[16]
Receptor tyrosine-protein kinase erbB-2 (ERBB2)	OTOAUNCK	ERBB2_HUMAN	Decreases Expression	[17]
Intercellular adhesion molecule 1 (ICAM1)	OTTOIX77	ICAM1_HUMAN	Increases Expression	[17]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Decreases Phosphorylation	[14]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Expression	[18]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[13]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[12]
Endoplasmic reticulum chaperone BiP (HSPA5)	OTFUIRAO	BIP_HUMAN	Increases Expression	[13]
Cadherin-1 (CDH1)	OTFJMXPM	CADH1_HUMAN	Decreases Expression	[14]
G2/mitotic-specific cyclin-B1 (CCNB1)	OT19S7E5	CCNB1_HUMAN	Increases Expression	[16]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Decreases Expression	[14]
Cadherin-2 (CDH2)	OTH0Y56P	CADH2_HUMAN	Decreases Expression	[14]
Cyclin-A2 (CCNA2)	OTPHHYZJ	CCNA2_HUMAN	Increases Expression	[16]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[19]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[17]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[17]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Phosphorylation	[14]
14-3-3 protein sigma (SFN)	OTLJCZ1U	1433S_HUMAN	Increases Expression	[13]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[13]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[18]
Serine/threonine-protein kinase mTOR (MTOR)	OTHH8KU7	MTOR_HUMAN	Decreases Expression	[16]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[7]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Increases Expression	[19]
Glycogen synthase kinase-3 beta (GSK3B)	OTL3L14B	GSK3B_HUMAN	Decreases Expression	[7]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Cleavage	[7]
BH3-interacting domain death agonist (BID)	OTOSHSHU	BID_HUMAN	Decreases Expression	[13]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Expression	[7]
Growth factor receptor-bound protein 2 (GRB2)	OTOP7LTE	GRB2_HUMAN	Decreases Expression	[14]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Increases Phosphorylation	[16]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[13]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[13]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Increases Expression	[16]
Son of sevenless homolog 1 (SOS1)	OTTCWXC3	SOS1_HUMAN	Decreases Expression	[14]
5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1)	OT7TNF0L	AAPK1_HUMAN	Affects Phosphorylation	[19]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Decreases Expression	[7]
Endonuclease G, mitochondrial (ENDOG)	OT5IM7B3	NUCG_HUMAN	Decreases Expression	[13]
Beclin-1 (BECN1)	OT4X293M	BECN1_HUMAN	Decreases Expression	[7]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Cleavage	[7]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Increases Expression	[13]
Inactive caspase-12 (CASP12)	OTY2W6FG	CASPC_HUMAN	Increases Cleavage	[13]
Microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B)	OTUYHB84	MLP3B_HUMAN	Increases Expression	[13]
Autophagy protein 5 (ATG5)	OT4T5SMS	ATG5_HUMAN	Decreases Expression	[7]

References

• [1] Loss of function mutations in VARS encoding cytoplasmic valyl-tRNA synthetase cause microcephaly, seizures, and progressive cerebral atrophy.Hum Genet. 2018 Apr;137(4):293-303. doi: 10.1007/s00439-018-1882-3. Epub 2018 Apr 24.
• [2] The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs. Curr Med Chem. 2008;15(2):161-71.
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022136)
• [5] Eurartesim - European Medicines Agency
• [6] Open-label crossover study of primaquine and dihydroartemisinin-piperaquine pharmacokinetics in healthy adult thai subjects. Antimicrob Agents Chemother. 2014 Dec;58(12):7340-6.
• [7] Tetrandrine induces apoptosis Via caspase-8, -9, and -3 and poly (ADP ribose) polymerase dependent pathways and autophagy through beclin-1/ LC3-I, II signaling pathways in human oral cancer HSC-3 cells. Environ Toxicol. 2016 Apr;31(4):395-406. doi: 10.1002/tox.22053. Epub 2014 Sep 30.
• [8] Tetrandrine: a novel calcium channel antagonist inhibits type I calcium channels in neuroblastoma cells. Neuropharmacology. 1991 Dec;30(12A):1325-31.
• [9] Integrated analysis on the physicochemical properties of dihydropyridine calcium channel blockers in grapefruit juice interactions. Curr Pharm Biotechnol. 2012 Jul;13(9):1705-17.
• [10] CYP3A5 mediates bioactivation and cytotoxicity of tetrandrine. Arch Toxicol. 2016 Jul;90(7):1737-48.
• [11] Pulmonary toxicity and metabolic activation of tetrandrine in CD-1 mice. Chem Res Toxicol. 2011 Dec 19;24(12):2142-52. doi: 10.1021/tx200290s. Epub 2011 Nov 11.
• [12] Anticancer effect of tetrandrine on primary cancer cells isolated from ascites and pleural fluids. Cancer Lett. 2008 Sep 8;268(1):166-75. doi: 10.1016/j.canlet.2008.03.059. Epub 2008 May 20.
• [13] Tetrandrine induces programmed cell death in human oral cancer CAL 27 cells through the reactive oxygen species production and caspase-dependent pathways and associated with beclin-1-induced cell autophagy. Environ Toxicol. 2017 Jan;32(1):329-343. doi: 10.1002/tox.22238. Epub 2016 Jan 29.
• [14] Tetrandrine inhibits human brain glioblastoma multiforme GBM 8401 cancer cell migration and invasion in vitro. Environ Toxicol. 2019 Apr;34(4):364-374. doi: 10.1002/tox.22691. Epub 2018 Dec 13.
• [15] Human precision-cut liver slices as a model to test antifibrotic drugs in the early onset of liver fibrosis. Toxicol In Vitro. 2016 Sep;35:77-85. doi: 10.1016/j.tiv.2016.05.012. Epub 2016 May 26.
• [16] Tetrandrine and cepharanthine induce apoptosis through caspase cascade regulation, cell cycle arrest, MAPK activation and PI3K/Akt/mTOR signal modification in glucocorticoid resistant human leukemia Jurkat T cells. Chem Biol Interact. 2019 Sep 1;310:108726. doi: 10.1016/j.cbi.2019.108726. Epub 2019 Jun 28.
• [17] Differentiation induction of human breast cancer cells by arsenite in combination with tetrandrine. Am J Transl Res. 2019 Dec 15;11(12):7310-7323. eCollection 2019.
• [18] [Effect of tetrandrine combined with daunorubicin on expressions of P21 and P-gp in K562/A02 cells]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2009 Oct;17(5):1179-82.
• [19] Antitumor activity of arsenite in combination with tetrandrine against human breast cancer cell line MDA-MB-231 in vitro and in vivo. Cancer Cell Int. 2018 Aug 13;18:113. doi: 10.1186/s12935-018-0613-0. eCollection 2018.