Details of the Drug Combination

General Information of Drug Combination (ID: DC9ET3K)

• Drug Combination Name: Alfacalcidol + Chloroquine
• Indication: Hepatoblastoma; Status: Investigative [1]
• Component Drugs:
  Alfacalcidol (DM1237M): N.A.
  Chloroquine (DMSI5CB): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: HB3
  Zero Interaction Potency (ZIP) Score: 0.286
  Bliss Independence Score: 4.931
  Loewe Additivity Score: 2.17
  LHighest Single Agent (HSA) Score: 2.09

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Alfacalcidol

Disease Entry	ICD 11	Status	REF
Hyperparathyroidism	5A51	Approved	[2]
Hypoparathyroidism	5A50	Approved	[3]
Renal osteodystrophy	N.A.	Approved	[4]

Alfacalcidol Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Vitamin D(3) 25-hydroxylase (CYP27A1)	DEBS639	CP27A_HUMAN	Metabolism	[11]
Cytochrome P450 2J2 (CYP2J2)	DERSX5P	CP2J2_HUMAN	Metabolism	[12]

Alfacalcidol Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial (CYP24A1)	OTG2T749	CP24A_HUMAN	Increases Expression	[13]
Toll-like receptor 2 (TLR2)	OTGO5P4R	TLR2_HUMAN	Decreases Expression	[14]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Increases Expression	[15]
Monocyte differentiation antigen CD14 (CD14)	OT83GJ47	CD14_HUMAN	Increases Expression	[14]
Retinoic acid receptor RXR-alpha (RXRA)	OTP1TBDM	RXRA_HUMAN	Affects Binding	[16]
Tumor necrosis factor receptor superfamily member 1B (TNFRSF1B)	OTDS2EAR	TNR1B_HUMAN	Decreases Expression	[15]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Hydroxylation	[17]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Affects Response To Substance	[18]

Indication(s) of Chloroquine

Disease Entry	ICD 11	Status	REF
Malaria	1F40-1F45	Approved	[5]
Plasmodium falciparum malaria	1F40	Approved	[6]
Plasmodium malariae malaria	N.A.	Approved	[6]
Plasmodium ovale malaria	N.A.	Approved	[6]
Systemic lupus erythematosus	4A40.0	Approved	[6]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[7]
Middle East Respiratory Syndrome (MERS)	1D64	Investigative	[8]
Severe acute respiratory syndrome (SARS)	1D65	Investigative	[9]

Chloroquine Interacts with 3 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	[19]
HUMAN glycosylation of host receptor (GHR)	TTZGK1R	N.A.	Inhibitor	[19]
Duffy antigen chemokine receptor (ACKR1)	TTKY2NS	ACKR1_HUMAN	Modulator	[20]

Chloroquine Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[21]
Multidrug and toxin extrusion protein 1 (SLC47A1)	DTZGT0P	S47A1_HUMAN	Substrate	[22]

Chloroquine Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[23]
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Metabolism	[24]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[25]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[23]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[26]

Chloroquine Interacts with 77 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Activity	[27]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Decreases Activity	[24]
Tumor necrosis factor receptor superfamily member 10A (TNFRSF10A)	OTBPCU2O	TR10A_HUMAN	Increases Expression	[28]
Inhibitor of nuclear factor kappa-B kinase subunit beta (IKBKB)	OT9RDS3H	IKKB_HUMAN	Decreases Expression	[29]
Inhibitor of nuclear factor kappa-B kinase subunit alpha (CHUK)	OTLF4ZB1	IKKA_HUMAN	Decreases Expression	[29]
Trans-Golgi network integral membrane protein 2 (TGOLN2)	OTM647IV	TGON2_HUMAN	Affects Localization	[30]
Claudin-1 (CLDN1)	OT27KV99	CLD1_HUMAN	Increases Expression	[31]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Decreases Expression	[32]
Metalloproteinase inhibitor 1 (TIMP1)	OTOXC51H	TIMP1_HUMAN	Decreases Expression	[33]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Expression	[34]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Increases Expression	[35]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Decreases Expression	[36]
Ferritin heavy chain (FTH1)	OT6IFS0O	FRIH_HUMAN	Increases Expression	[33]
Receptor tyrosine-protein kinase erbB-2 (ERBB2)	OTOAUNCK	ERBB2_HUMAN	Decreases Expression	[32]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Activity	[37]
Sodium/potassium-transporting ATPase subunit alpha-1 (ATP1A1)	OTCJ458Q	AT1A1_HUMAN	Increases Expression	[38]
Apolipoprotein D (APOD)	OTT77XW8	APOD_HUMAN	Affects Localization	[39]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Expression	[34]
Cathepsin B (CTSB)	OTP9G5QB	CATB_HUMAN	Decreases Activity	[40]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Expression	[28]
72 kDa type IV collagenase (MMP2)	OT5NIWA2	MMP2_HUMAN	Decreases Expression	[41]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[42]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[35]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[35]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Decreases Expression	[41]
Glutamine synthetase (GLUL)	OTYGTCGF	GLNA_HUMAN	Decreases Expression	[43]
CCAAT/enhancer-binding protein beta (CEBPB)	OTM9MQIA	CEBPB_HUMAN	Increases Expression	[44]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Decreases Expression	[29]
Cation-dependent mannose-6-phosphate receptor (M6PR)	OTFEWOSB	MPRD_HUMAN	Affects Localization	[30]
Receptor tyrosine-protein kinase erbB-3 (ERBB3)	OTRSST0A	ERBB3_HUMAN	Decreases Expression	[32]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[45]
Calreticulin (CALR)	OTYD2TR1	CALR_HUMAN	Increases Expression	[44]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[45]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Phosphorylation	[46]
Multidrug resistance-associated protein 1 (ABCC1)	OTGUN89S	MRP1_HUMAN	Decreases Expression	[28]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[44]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[47]
Aquaporin-2 (AQP2)	OTQLBKK6	AQP2_HUMAN	Decreases Expression	[48]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[49]
Collagenase 3 (MMP13)	OTY8BZIE	MMP13_HUMAN	Increases Expression	[41]
Coatomer subunit delta (ARCN1)	OTJ96STE	COPD_HUMAN	Affects Localization	[30]
Eotaxin (CCL11)	OT3BIFPK	CCL11_HUMAN	Decreases Secretion	[50]
Microsomal triglyceride transfer protein large subunit (MTTP)	OTNUVSDT	MTP_HUMAN	Increases Expression	[51]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Cleavage	[49]
Gamma-aminobutyric acid receptor-associated protein-like 2 (GABARAPL2)	OTS7YVHF	GBRL2_HUMAN	Increases Expression	[43]
Interleukin-2 (IL2)	OTGI4NSA	IL2_HUMAN	Decreases Expression	[52]
Rho-related GTP-binding protein RhoB (RHOB)	OTHQFQF7	RHOB_HUMAN	Increases Expression	[43]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Decreases Expression	[29]
Recombining binding protein suppressor of hairless (RBPJ)	OTD7CUG0	SUH_HUMAN	Increases Expression	[53]
Lymphotoxin-beta (LTB)	OTUFS8CF	TNFC_HUMAN	Increases Expression	[35]
Golgin subfamily A member 2 (GOLGA2)	OT5S9KYM	GOGA2_HUMAN	Affects Localization	[30]
BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)	OT4SO7J4	BNIP3_HUMAN	Increases Expression	[54]
Serine-protein kinase ATM (ATM)	OTQVOHLT	ATM_HUMAN	Increases Phosphorylation	[55]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Increases Expression	[56]
Solute carrier family 12 member 1 (SLC12A1)	OT6YSX0G	S12A1_HUMAN	Decreases Expression	[48]
Nuclear receptor coactivator 4 (NCOA4)	OTRVU0UA	NCOA4_HUMAN	Increases Expression	[33]
Beclin-1 (BECN1)	OT4X293M	BECN1_HUMAN	Decreases Expression	[57]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Cleavage	[28]
Early endosome antigen 1 (EEA1)	OTIBXC1B	EEA1_HUMAN	Affects Localization	[30]
Occludin (OCLN)	OTSUTVWL	OCLN_HUMAN	Increases Expression	[31]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Decreases Expression	[45]
ATP-binding cassette sub-family C member 2 (ABCC2)	OTJSIGV5	MRP2_HUMAN	Decreases Expression	[28]
Tribbles homolog 3 (TRIB3)	OTG5OS7X	TRIB3_HUMAN	Increases Expression	[44]
Microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B)	OTUYHB84	MLP3B_HUMAN	Increases Expression	[58]
Autophagy protein 5 (ATG5)	OT4T5SMS	ATG5_HUMAN	Increases Expression	[40]
Microtubule-associated proteins 1A/1B light chain 3A (MAP1LC3A)	OTPMGIU4	MLP3A_HUMAN	Increases Expression	[59]
Toll-like receptor 9 (TLR9)	OTFZ45HX	TLR9_HUMAN	Increases Expression	[41]
Toll-like receptor 8 (TLR8)	OTEJRL9C	TLR8_HUMAN	Decreases Activity	[60]
NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SIRT3)	OTMEF544	SIR3_HUMAN	Increases Stability	[61]
Toll-like receptor 7 (TLR7)	OT3HZV7Z	TLR7_HUMAN	Decreases Activity	[60]
Programmed cell death 1 ligand 1 (CD274)	OTJ0VFDL	PD1L1_HUMAN	Decreases Expression	[28]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Decreases Expression	[28]
NF-kappa-B essential modulator (IKBKG)	OTNWJWSD	NEMO_HUMAN	Decreases Expression	[29]
Solute carrier organic anion transporter family member 1B1 (SLCO1B1)	OTNEN8QK	SO1B1_HUMAN	Affects Localization	[38]
Porphobilinogen deaminase (HMBS)	OT3P47DC	HEM3_HUMAN	Increases Response To Substance	[62]
Cytochrome P450 2C8 (CYP2C8)	OTHCWT42	CP2C8_HUMAN	Increases Metabolism	[63]
Linker for activation of T-cells family member 2 (LAT2)	OTWJDKIH	NTAL_HUMAN	Increases Response To Substance	[64]

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] X-Linked Hypophosphatemia. 2012 Feb 9 [updated 2023 Dec 14]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [3] Auditing the Efficacy and Safety of Alfacalcidol and Calcium Therapy in Idiopathic Hypoparathyroidism. J Clin Endocrinol Metab. 2019 Apr 1;104(4):1325-1335.
• [4] Cross-linked C-terminal telopeptide of type I collagen in serum before and after treatment with alfacalcidol and calcium carbonate in early and moderate chronic renal failure. Nephron. 2002 Oct;92(2):304-8.
• [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: 5535).
• [6] Chloroquine FDA Label
• [7] ClinicalTrials.gov (NCT04360759) Chloroquine Outpatient Treatment Evaluation for HIV-Covid-19. U.S. National Institutes of Health.
• [8] Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov. 2016 May;15(5):327-47.
• [9] Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat Rev Drug Discov. 2020 Mar;19(3):149-150.
• [10] Functional evolution of the vitamin D and pregnane X receptors. BMC Evol Biol. 2007 Nov 12;7:222. doi: 10.1186/1471-2148-7-222.
• [11] Kidney microsomal 25- and 1alpha-hydroxylase in vitamin D metabolism: catalytic properties, molecular cloning, cellular localization and expression during development. Biochim Biophys Acta. 2002 Feb 28;1580(2-3):133-44.
• [12] Characterization of rat and human CYP2J enzymes as Vitamin D 25-hydroxylases. Steroids. 2006 Oct;71(10):849-56.
• [13] Dermal fibroblasts pretreated with a sterol Delta7-reductase inhibitor produce 25-hydroxyvitamin D3 upon UVB irradiation. J Photochem Photobiol B. 2006 Oct 2;85(1):72-8.
• [14] 1-alpha-calcidol modulates major human monocyte antigens and toll-like receptors TLR 2 and TLR4 in vitro. Eur J Med Res. 2005 Apr 20;10(4):179-82.
• [15] Supplementation with Alfacalcidol increases protein intake and serum albumin concentration in patients undergoing hemodialysis with hpoalbumineamia. Blood Purif. 2004;22(2):210-5. doi: 10.1159/000076855.
• [16] Hydrogen/deuterium exchange reveals distinct agonist/partial agonist receptor dynamics within vitamin D receptor/retinoid X receptor heterodimer. Structure. 2010 Oct 13;18(10):1332-41. doi: 10.1016/j.str.2010.07.007.
• [17] CYP3A4 is a human microsomal vitamin D 25-hydroxylase. J Bone Miner Res. 2004 Apr;19(4):680-8.
• [18] Association of transforming growth factor beta1 genotype with therapeutic response to active vitamin D for postmenopausal osteoporosis. J Bone Miner Res. 2000 Mar;15(3):415-20. doi: 10.1359/jbmr.2000.15.3.415.
• [19] Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020 Mar;30(3):269-271.
• [20] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [21] Improving the prediction of the brain disposition for orally administered drugs using BDDCS. Adv Drug Deliv Rev. 2012 Jan;64(1):95-109.
• [22] Molecular mechanism of renal tubular secretion of the antimalarial drug chloroquine. Antimicrob Agents Chemother. 2011 Jul;55(7):3091-8.
• [23] Cytochrome P450 2C8 and CYP3A4/5 are involved in chloroquine metabolism in human liver microsomes. Arch Pharm Res. 2003 Aug;26(8):631-7.
• [24] In vitro metabolism of chloroquine: identification of CYP2C8, CYP3A4, and CYP2D6 as the main isoforms catalyzing N-desethylchloroquine formation. Drug Metab Dispos. 2003 Jun;31(6):748-54.
• [25] Halofantrine and chloroquine inhibit CYP2D6 activity in healthy Zambians. Br J Clin Pharmacol. 1998 Mar;45(3):315-7.
• [26] Short communication: high prevalence of the cytochrome P450 2C8*2 mutation in Northern Ghana. Trop Med Int Health. 2005 Dec;10(12):1271-3.
• [27] 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.
• [28] Autophagy inhibition upregulates CD4(+) tumor infiltrating lymphocyte expression via miR-155 regulation and TRAIL activation. Mol Oncol. 2016 Dec;10(10):1516-1531. doi: 10.1016/j.molonc.2016.08.005. Epub 2016 Sep 16.
• [29] Niclosamide, an anti-helminthic molecule, downregulates the retroviral oncoprotein Tax and pro-survival Bcl-2 proteins in HTLV-1-transformed T lymphocytes. Biochem Biophys Res Commun. 2015 Aug 14;464(1):221-228. doi: 10.1016/j.bbrc.2015.06.120. Epub 2015 Jun 23.
• [30] Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion. Autophagy. 2018;14(8):1435-1455. doi: 10.1080/15548627.2018.1474314. Epub 2018 Jul 20.
• [31] 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.
• [32] Sulindac metabolites induce proteosomal and lysosomal degradation of the epidermal growth factor receptor. Cancer Prev Res (Phila). 2010 Apr;3(4):560-72. doi: 10.1158/1940-6207.CAPR-09-0159. Epub 2010 Mar 23.
• [33] 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.
• [34] Calcitriol-mediated hypercalcaemia and increased interleukins in a patient with sarcoid myopathy. Clin Rheumatol. 1999;18(6):488-91. doi: 10.1007/s100670050144.
• [35] 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.
• [36] Profiling the immunotoxicity of chemicals based on in vitro evaluation by a combination of the Multi-ImmunoTox assay and the IL-8 Luc assay. Arch Toxicol. 2018 Jun;92(6):2043-2054. doi: 10.1007/s00204-018-2199-7. Epub 2018 Mar 29.
• [37] High-throughput measurement of the Tp53 response to anticancer drugs and random compounds using a stably integrated Tp53-responsive luciferase reporter. Carcinogenesis. 2002 Jun;23(6):949-57. doi: 10.1093/carcin/23.6.949.
• [38] Downregulation of Organic Anion Transporting Polypeptide (OATP) 1B1 Transport Function by Lysosomotropic Drug Chloroquine: Implication in OATP-Mediated Drug-Drug Interactions. Mol Pharm. 2016 Mar 7;13(3):839-51. doi: 10.1021/acs.molpharmaceut.5b00763. Epub 2016 Feb 1.
• [39] Protecting cells by protecting their vulnerable lysosomes: Identification of a new mechanism for preserving lysosomal functional integrity upon oxidative stress. PLoS Genet. 2017 Feb 9;13(2):e1006603. doi: 10.1371/journal.pgen.1006603. eCollection 2017 Feb.
• [40] Chloroquine aggravates the arsenic trioxide (As2O3)-induced apoptosis of acute promyelocytic leukemia NB4 cells via inhibiting lysosomal degradation in vitro. Eur Rev Med Pharmacol Sci. 2018 Oct;22(19):6412-6421. doi: 10.26355/eurrev_201810_16054.
• [41] Chloroquine has tumor-inhibitory and tumor-promoting effects in triple-negative breast cancer. Oncol Lett. 2013 Dec;6(6):1665-1672. doi: 10.3892/ol.2013.1602. Epub 2013 Oct 4.
• [42] NDRG1 inhibition sensitizes osteosarcoma cells to combretastatin A-4 through targeting autophagy. Cell Death Dis. 2017 Sep 14;8(9):e3048. doi: 10.1038/cddis.2017.438.
• [43] Toxicoproteomics reveals an effect of clozapine on autophagy in human liver spheroids. Toxicol Mech Methods. 2023 Jun;33(5):401-410. doi: 10.1080/15376516.2022.2156005. Epub 2022 Dec 19.
• [44] Increasing intratumor C/EBP- LIP and nitric oxide levels overcome resistance to doxorubicin in triple negative breast cancer. J Exp Clin Cancer Res. 2018 Nov 27;37(1):286. doi: 10.1186/s13046-018-0967-0.
• [45] Inhibition of autophagic flux differently modulates cannabidiol-induced death in 2D and 3D glioblastoma cell cultures. Sci Rep. 2020 Feb 14;10(1):2687. doi: 10.1038/s41598-020-59468-4.
• [46] Effect of toll-like receptor 7 and 9 targeted therapy to prevent the development of hepatocellular carcinoma. Liver Int. 2015 Mar;35(3):1063-76. doi: 10.1111/liv.12626. Epub 2014 Jul 30.
• [47] Control of mammary tumor cell growth in vitro by novel cell differentiation and apoptosis agents. Breast Cancer Res Treat. 2002 Sep;75(2):107-17. doi: 10.1023/a:1019698807564.
• [48] Chronic use of chloroquine disrupts the urine concentration mechanism by lowering cAMP levels in the inner medulla. Am J Physiol Renal Physiol. 2012 Sep 15;303(6):F900-5. doi: 10.1152/ajprenal.00547.2011. Epub 2012 Jul 11.
• [49] The dual PI3K/mTOR inhibitor NVP-BEZ235 and chloroquine synergize to trigger apoptosis via mitochondrial-lysosomal cross-talk. Int J Cancer. 2013 Jun 1;132(11):2682-93. doi: 10.1002/ijc.27935. Epub 2012 Dec 4.
• [50] Paradoxical Effect of Chloroquine Treatment in Enhancing Chikungunya Virus Infection. Viruses. 2018 May 17;10(5):268. doi: 10.3390/v10050268.
• [51] Cadmium induces triglyceride levels via microsomal triglyceride transfer protein (MTTP) accumulation caused by lysosomal deacidification regulated by endoplasmic reticulum (ER) Ca(2+) homeostasis. Chem Biol Interact. 2021 Oct 1;348:109649. doi: 10.1016/j.cbi.2021.109649. Epub 2021 Sep 10.
• [52] Chloroquine inhibits T cell proliferation by interfering with IL-2 production and responsiveness. Clin Exp Immunol. 1995 Oct;102(1):144-51. doi: 10.1111/j.1365-2249.1995.tb06648.x.
• [53] Presenilin-2 regulates the degradation of RBP-Jk protein through p38 mitogen-activated protein kinase. J Cell Sci. 2012 Mar 1;125(Pt 5):1296-308. doi: 10.1242/jcs.095984. Epub 2012 Feb 2.
• [54] Inhibition of cholesterol metabolism underlies synergy between mTOR pathway inhibition and chloroquine in bladder cancer cells. Oncogene. 2016 Aug 25;35(34):4518-28. doi: 10.1038/onc.2015.511. Epub 2016 Feb 8.
• [55] Ataxia telangiectasia-mutated and p53 are potential mediators of chloroquine-induced resistance to mammary carcinogenesis. Cancer Res. 2007 Dec 15;67(24):12026-33. doi: 10.1158/0008-5472.CAN-07-3058.
• [56] Inhibition of autophagy potentiates the antitumor effect of the multikinase inhibitor sorafenib in hepatocellular carcinoma. Int J Cancer. 2012 Aug 1;131(3):548-57. doi: 10.1002/ijc.26374. Epub 2011 Sep 12.
• [57] Antitumor activity of chloroquine in combination with Cisplatin in human gastric cancer xenografts. Asian Pac J Cancer Prev. 2015;16(9):3907-12. doi: 10.7314/apjcp.2015.16.9.3907.
• [58] Critical role of FoxO3a in alcohol-induced autophagy and hepatotoxicity. Am J Pathol. 2013 Dec;183(6):1815-1825. doi: 10.1016/j.ajpath.2013.08.011. Epub 2013 Oct 1.
• [59] Riluzole induces AR degradation via endoplasmic reticulum stress pathway in androgen-dependent and castration-resistant prostate cancer cells. Prostate. 2019 Feb;79(2):140-150. doi: 10.1002/pros.23719. Epub 2018 Oct 2.
• [60] HCV RNA Activates APCs via TLR7/TLR8 While Virus Selectively Stimulates Macrophages Without Inducing Antiviral Responses. Sci Rep. 2016 Jul 7;6:29447. doi: 10.1038/srep29447.
• [61] Effects of SIDT2 on the miR-25/NOX4/HuR axis and SIRT3 mRNA stability lead to ROS-mediated TNF- expression in hydroquinone-treated leukemia cells. Cell Biol Toxicol. 2023 Oct;39(5):2207-2225. doi: 10.1007/s10565-022-09705-5. Epub 2022 Mar 18.
• [62] Precipitation of acute intermittent porphyria by chloroquin. Indian Pediatr. 1996 Mar;33(3):241-3.
• [63] CYP2C8 and antimalaria drug efficacy. Pharmacogenomics. 2007 Feb;8(2):187-98. doi: 10.2217/14622416.8.2.187.
• [64] NTAL is associated with treatment outcome, cell proliferation and differentiation in acute promyelocytic leukemia. Sci Rep. 2020 Jun 25;10(1):10315. doi: 10.1038/s41598-020-66223-2.