Details of the Drug Combination

General Information of Drug Combination (ID: DC9VG9D)

• Drug Combination Name: Lovastatin + Interferon Alfa-2b
• Indication: Melanoma; Status: Phase 1 [1]
• Component Drugs:
  Lovastatin (DM9OZWQ): Small molecular drug
  Interferon Alfa-2b (DMWCQP4): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Lovastatin

Disease Entry	ICD 11	Status	REF
Arteriosclerosis	BD40	Approved	[2]
Hypercholesterolaemia	5C80.0	Approved	[3]
Hyperlipidemia	5C80.Z	Approved	[2]
Hyperlipidemia, familial combined, LPL related	N.A.	Approved	[2]
Hypertriglyceridemia	5C80.1	Approved	[2]
Melanoma	2C30	Approved	[2]
X-linked chondrodysplasia punctata 2	N.A.	Approved	[2]
Cardiovascular disease	BA00-BE2Z	Phase 3	[4]
Smith-Lemli-Opitz syndrome	N.A.	Investigative	[2]

Lovastatin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
HMG-CoA reductase (HMGCR)	TTPADOQ	HMDH_HUMAN	Inhibitor	[6]

Lovastatin Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[7]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[8]

Lovastatin Interacts with 7 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[9]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[10]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[10]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[10]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[10]
UDP-glucuronosyltransferase 1A3 (UGT1A3)	DEF2WXN	UD13_HUMAN	Metabolism	[10]
Serum paraoxonase/lactonase 3 (PON3)	DETXQZ1	PON3_HUMAN	Metabolism	[11]

Lovastatin Interacts with 73 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C8 (CYP2C8)	OTHCWT42	CP2C8_HUMAN	Decreases Activity	[12]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[13]
Serum paraoxonase/lactonase 3 (PON3)	OT80W9TA	PON3_HUMAN	Increases Hydrolysis	[14]
Solute carrier organic anion transporter family member 1B1 (SLCO1B1)	OTNEN8QK	SO1B1_HUMAN	Decreases Activity	[15]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Transport	[15]
3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)	OTRT3F3U	HMDH_HUMAN	Increases Expression	[16]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[17]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[18]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[19]
Squalene synthase (FDFT1)	OTGDISIT	FDFT_HUMAN	Increases Activity	[20]
ATP-binding cassette sub-family C member 2 (ABCC2)	OTJSIGV5	MRP2_HUMAN	Decreases Activity	[15]
Insulin-induced gene 1 protein (INSIG1)	OTZF5X1D	INSI1_HUMAN	Increases Expression	[16]
Phospholipid-transporting ATPase ABCA1 (ABCA1)	OT94G6BQ	ABCA1_HUMAN	Increases Expression	[16]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[21]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[22]
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[23]
GTPase NRas (NRAS)	OTVQ1DG3	RASN_HUMAN	Decreases Prenylation	[24]
GTPase HRas (HRAS)	OTWQN0DP	RASH_HUMAN	Decreases Prenylation	[24]
GTPase KRas (KRAS)	OT78QCN8	RASK_HUMAN	Decreases Prenylation	[24]
Low-density lipoprotein receptor (LDLR)	OTH559LU	LDLR_HUMAN	Increases Expression	[25]
Thyroglobulin (TG)	OT3ELHIJ	THYG_HUMAN	Increases Secretion	[26]
RAF proto-oncogene serine/threonine-protein kinase (RAF1)	OT51LSFO	RAF1_HUMAN	Decreases Activity	[27]
Apolipoprotein B-100 (APOB)	OTH0UOCZ	APOB_HUMAN	Decreases Secretion	[25]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[28]
Amyloid-beta precursor protein (APP)	OTKFD7R4	A4_HUMAN	Increases Cleavage	[29]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Phosphorylation	[30]
Tyrosine 3-monooxygenase (TH)	OT6ZORKP	TY3H_HUMAN	Increases Expression	[31]
72 kDa type IV collagenase (MMP2)	OT5NIWA2	MMP2_HUMAN	Decreases Expression	[27]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[32]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[17]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[33]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Decreases Expression	[27]
CD44 antigen (CD44)	OT9TTJ41	CD44_HUMAN	Decreases Expression	[28]
Neuromodulin (GAP43)	OT2OTGGV	NEUM_HUMAN	Increases Expression	[31]
Lamin-B1 (LMNB1)	OT100T3P	LMNB1_HUMAN	Decreases Farnesylation	[34]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[35]
Cyclin-dependent kinase 2 (CDK2)	OTB5DYYZ	CDK2_HUMAN	Decreases Activity	[30]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Activity	[27]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Activity	[27]
G1/S-specific cyclin-D3 (CCND3)	OTNKPQ22	CCND3_HUMAN	Decreases Expression	[30]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Phosphorylation	[36]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Increases Expression	[17]
Sterol regulatory element-binding protein 1 (SREBF1)	OTWBRPAI	SRBP1_HUMAN	Increases Expression	[37]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Affects Localization	[17]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[35]
Caspase-2 (CASP2)	OTUDYSPP	CASP2_HUMAN	Increases Activity	[18]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Increases Expression	[30]
Fatty acid synthase (FASN)	OTFII9KG	FAS_HUMAN	Increases Expression	[25]
Centromere protein F (CENPF)	OT7AG0SW	CENPF_HUMAN	Increases Expression	[38]
Glycogen synthase kinase-3 beta (GSK3B)	OTL3L14B	GSK3B_HUMAN	Decreases Phosphorylation	[39]
Tumor necrosis factor ligand superfamily member 10 (TNFSF10)	OT4PXBTA	TNF10_HUMAN	Increases Response To Substance	[40]
Caspase-6 (CASP6)	OTXLD3EC	CASP6_HUMAN	Increases Activity	[41]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN)	OTOWDUNT	PTEN_HUMAN	Increases Expression	[36]
Cell division control protein 42 homolog (CDC42)	OT5QBC5M	CDC42_HUMAN	Increases Expression	[23]
Transforming protein RhoA (RHOA)	OT6YOJ9N	RHOA_HUMAN	Decreases Prenylation	[24]
Actin, aortic smooth muscle (ACTA2)	OTEDLG8E	ACTA_HUMAN	Decreases Expression	[42]
Rho-related GTP-binding protein RhoB (RHOB)	OTHQFQF7	RHOB_HUMAN	Decreases Prenylation	[24]
Ras-related protein Rap-1A (RAP1A)	OT5RH6TI	RAP1A_HUMAN	Increases Expression	[38]
Ras-related C3 botulinum toxin substrate 1 (RAC1)	OTKRO61U	RAC1_HUMAN	Decreases Activity	[27]
HLA class II histocompatibility antigen, DR beta 3 chain (HLA-DRB3)	OT5PM9N7	DRB3_HUMAN	Affects Expression	[43]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[33]
Sterol regulatory element-binding protein 2 (SREBF2)	OTBXUNPL	SRBP2_HUMAN	Increases Localization	[25]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Affects Activity	[44]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[45]
Lymphoid enhancer-binding factor 1 (LEF1)	OTWS5I5H	LEF1_HUMAN	Affects Localization	[39]
A-kinase anchor protein 7 isoforms alpha and beta (AKAP7)	OT0L3PZ6	AKA7A_HUMAN	Decreases Response To Substance	[46]
Beta-parvin (PARVB)	OT9OGVWX	PARVB_HUMAN	Decreases Response To Substance	[46]
Metalloreductase STEAP2 (STEAP2)	OTGE9ETG	STEA2_HUMAN	Decreases Response To Substance	[46]
Interleukin-2 (IL2)	OTGI4NSA	IL2_HUMAN	Increases ADR	[47]
Alanine aminotransferase 1 (GPT)	OTOXOA0Q	ALAT1_HUMAN	Increases ADR	[47]
Phosphatidate phosphatase LPIN2 (LPIN2)	OTRRTMXX	LPIN2_HUMAN	Decreases Response To Substance	[46]
ELL-associated factor 2 (EAF2)	OTSOET5L	EAF2_HUMAN	Decreases Response To Substance	[46]
Ankyrin-2 (ANK2)	OTWB4R1Y	ANK2_HUMAN	Decreases Response To Substance	[46]

Indication(s) of Interferon Alfa-2b

Disease Entry	ICD 11	Status	REF
Melanoma	2C30	Approved	[5]

Interferon Alfa-2b Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Interferon-alpha 2 (IFNA2)	TTSIUJ9	IFNA2_HUMAN	Modulator	[49]

Interferon Alfa-2b Interacts with 6 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
2'-5'-oligoadenylate synthase 1 (OAS1)	OT8ZLOCY	OAS1_HUMAN	Increases Expression	[48]
Interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2)	OT8DXMS3	E2AK2_HUMAN	Increases Expression	[48]
Tyrosine-protein kinase JAK1 (JAK1)	OT0X3D17	JAK1_HUMAN	Increases Expression	[48]
Signal transducer and activator of transcription 3 (STAT3)	OTAAGKYZ	STAT3_HUMAN	Increases Phosphorylation	[48]
Signal transducer and activator of transcription 1-alpha/beta (STAT1)	OTLMBUZ6	STAT1_HUMAN	Increases Expression	[48]
Signal transducer and activator of transcription 2 (STAT2)	OTO9G2RZ	STAT2_HUMAN	Increases Phosphorylation	[48]

References

• [1] ClinicalTrials.gov (NCT00963664) Evaluation of Interferon-Lovastatin Therapy for Malignant Melanoma
• [2] Lovastatin FDA Label
• [3] 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: 2739).
• [4] Clinical pipeline report, company report or official report of CardioPharma Wilmington.
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [6] Microarray and biochemical analysis of lovastatin-induced apoptosis of squamous cell carcinomas. Neoplasia. 2002 Jul-Aug;4(4):337-46.
• [7] 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.
• [8] A novel human hepatic organic anion transporting polypeptide (OATP2). Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters. J Biol Chem. 1999 Dec 24;274(52):37161-8.
• [9] Metabolic interactions with statins. Tidsskr Nor Laegeforen. 2001 Jan 20;121(2):189-93.
• [10] Pharmacogenomics of statins: understanding susceptibility to adverse effects. Pharmgenomics Pers Med. 2016 Oct 3;9:97-106.
• [11] Paraoxonases-1, -2 and -3: what are their functions? Chem Biol Interact. 2016 Nov 25;259(Pt B):51-62.
• [12] Examination of 209 drugs for inhibition of cytochrome P450 2C8. J Clin Pharmacol. 2005 Jan;45(1):68-78.
• [13] Receptor-dependent regulation of the CYP3A4 gene. Toxicology. 2002 Dec 27;181-182:199-202.
• [14] Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities. J Lipid Res. 2005 Jun;46(6):1239-47. doi: 10.1194/jlr.M400511-JLR200. Epub 2005 Mar 16.
• [15] Differential interaction of 3-hydroxy-3-methylglutaryl-coa reductase inhibitors with ABCB1, ABCC2, and OATP1B1. Drug Metab Dispos. 2005 Apr;33(4):537-46.
• [16] Desmosterol can replace cholesterol in sustaining cell proliferation and regulating the SREBP pathway in a sterol-Delta24-reductase-deficient cell line. Biochem J. 2009 May 13;420(2):305-15.
• [17] Lovastatin lactone elicits human lung cancer cell apoptosis via a COX-2/PPAR-dependent pathway. Oncotarget. 2016 Mar 1;7(9):10345-62. doi: 10.18632/oncotarget.7213.
• [18] Lovastatin induces apoptosis of anaplastic thyroid cancer cells via inhibition of protein geranylgeranylation and de novo protein synthesis. Endocrinology. 2003 Sep;144(9):3852-9. doi: 10.1210/en.2003-0098.
• [19] Statins activate the mitochondrial pathway of apoptosis in human lymphoblasts and myeloma cells. Carcinogenesis. 2005 May;26(5):883-91. doi: 10.1093/carcin/bgi036. Epub 2005 Feb 10.
• [20] Pravastatin inhibited the cholesterol synthesis in human hepatoma cell line Hep G2 less than simvastatin and lovastatin, which is reflected in the upregulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase and squalene synthase. Biochem Pharmacol. 1993 Jun 9;45(11):2203-8.
• [21] A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol Sci. 2013 Nov;136(1):216-41.
• [22] Survivin down-regulation plays a crucial role in 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor-induced apoptosis in cancer. J Biol Chem. 2007 Jul 6;282(27):19273-81. doi: 10.1074/jbc.M610350200. Epub 2007 May 1.
• [23] Statins induce apoptosis in ovarian cancer cells through activation of JNK and enhancement of Bim expression. Cancer Chemother Pharmacol. 2009 May;63(6):997-1005. doi: 10.1007/s00280-008-0830-7. Epub 2008 Sep 3.
• [24] Combining prenylation inhibitors causes synergistic cytotoxicity, apoptosis and disruption of RAS-to-MAP kinase signalling in multiple myeloma cells. Br J Haematol. 2005 Sep;130(6):912-25. doi: 10.1111/j.1365-2141.2005.05696.x.
• [25] Effect of atorvastatin, simvastatin, and lovastatin on the metabolism of cholesterol and triacylglycerides in HepG2 cells. Biochem Pharmacol. 2001 Dec 1;62(11):1545-55. doi: 10.1016/s0006-2952(01)00790-0.
• [26] Lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells. J Clin Endocrinol Metab. 2003 Jul;88(7):3021-6. doi: 10.1210/jc.2002-021834.
• [27] Simvastatin and lovastatin inhibit breast cell invasion induced by H-Ras. Oncol Rep. 2009 May;21(5):1317-22. doi: 10.3892/or_00000357.
• [28] Simvastatin prevents skeletal metastasis of breast cancer by an antagonistic interplay between p53 and CD44. J Biol Chem. 2011 Apr 1;286(13):11314-27. doi: 10.1074/jbc.M110.193714. Epub 2011 Jan 3.
• [29] Protection against the Neurotoxic Effects of -Amyloid Peptide on Cultured Neuronal Cells by Lovastatin Involves Elevated Expression of 7 Nicotinic Acetylcholine Receptors and Activating Phosphorylation of Protein Kinases. Am J Pathol. 2018 Apr;188(4):1081-1093. doi: 10.1016/j.ajpath.2017.11.020. Epub 2018 Jan 16.
• [30] Lovastatin inhibits G1/S transition of normal human B-lymphocytes independent of apoptosis. Exp Cell Res. 1999 Oct 10;252(1):144-53. doi: 10.1006/excr.1999.4608.
• [31] Lovastatin induces neuronal differentiation and apoptosis of embryonal carcinoma and neuroblastoma cells: enhanced differentiation and apoptosis in combination with dbcAMP. Mol Cell Biochem. 2010 Dec;345(1-2):1-11. doi: 10.1007/s11010-010-0553-z. Epub 2010 Aug 9.
• [32] Simvastatin-dependent up-regulation of heme oxygenase-1 via mRNA stabilization in human endothelial cells. Eur J Pharm Sci. 2010 Sep 11;41(1):118-24. doi: 10.1016/j.ejps.2010.05.021. Epub 2010 Jun 8.
• [33] Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells. Clin Cancer Res. 1999 Aug;5(8):2223-9.
• [34] Apoptosis and cell-cycle arrest in human and murine tumor cells are initiated by isoprenoids. J Nutr. 1999 Apr;129(4):804-13. doi: 10.1093/jn/129.4.804.
• [35] In vitro mechanisms of lovastatin on lung cancer cell lines as a potential chemopreventive agent. Lung. 2008 Jan-Feb;186(1):45-54. doi: 10.1007/s00408-007-9053-7. Epub 2007 Nov 22.
• [36] Increased PTEN expression due to transcriptional activation of PPARgamma by Lovastatin and Rosiglitazone. Int J Cancer. 2006 May 15;118(10):2390-8. doi: 10.1002/ijc.21799.
• [37] Indirect co-cultivation of HepG2 with differentiated THP-1 cells induces AHR signalling and release of pro-inflammatory cytokines. Toxicol In Vitro. 2020 Oct;68:104957. doi: 10.1016/j.tiv.2020.104957. Epub 2020 Jul 30.
• [38] Synergistic interaction of lovastatin and paclitaxel in human cancer cells. Mol Cancer Ther. 2001 Dec;1(2):141-9.
• [39] Lovastatin protects human neurons against Abeta-induced toxicity and causes activation of beta-catenin-TCF/LEF signaling. Neurosci Lett. 2007 Feb 2;412(3):211-6. doi: 10.1016/j.neulet.2006.07.045. Epub 2007 Jan 17.
• [40] Lovastatin sensitized human glioblastoma cells to TRAIL-induced apoptosis. J Neurooncol. 2008 Feb;86(3):273-83. doi: 10.1007/s11060-007-9475-3. Epub 2007 Oct 11.
• [41] Lovastatin-induced apoptosis in thyroid cells: involvement of cytochrome c and lamin B. Eur J Endocrinol. 2001 Nov;145(5):645-50. doi: 10.1530/eje.0.1450645.
• [42] Inhibitory effects of clinical reagents having anti-oxidative activity on transforming growth factor-1-induced expression of -smooth muscle actin in human fetal lung fibroblasts. J Toxicol Sci. 2011;36(6):733-40. doi: 10.2131/jts.36.733.
• [43] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [44] Comparative evaluation of HERG currents and QT intervals following challenge with suspected torsadogenic and nontorsadogenic drugs. J Pharmacol Exp Ther. 2006 Mar;316(3):1098-106. doi: 10.1124/jpet.105.093393. Epub 2005 Nov 8.
• [45] Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.
• [46] NCI60 cancer cell line panel data and RNAi analysis help identify EAF2 as a modulator of simvastatin and lovastatin response in HCT-116 cells. PLoS One. 2011 Apr 4;6(4):e18306. doi: 10.1371/journal.pone.0018306.
• [47] 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.
• [48] 6-Hydroxy-3-O-methyl-kaempferol 6-O-glucopyranoside potentiates the anti-proliferative effect of interferon / by promoting activation of the JAK/STAT signaling by inhibiting SOCS3 in hepatocellular carcinoma cells. Toxicol Appl Pharmacol. 2017 Dec 1;336:31-39. doi: 10.1016/j.taap.2017.10.004. Epub 2017 Oct 12.
• [49] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.