Details of the Drug Combination

General Information of Drug Combination (ID: DCJZL7O)

• Drug Combination Name: Sorafenib + Aminolevulinic Acid Hydrochloride
• Indication: Mixed endometrioid and clear cell carcinoma; Status: Investigative [1]
• Component Drugs:
  Sorafenib (DMS8IFC): Small molecular drug
  Aminolevulinic Acid Hydrochloride (DMWNHPC): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: IGROV1
  Zero Interaction Potency (ZIP) Score: 9.76
  Bliss Independence Score: 11
  Loewe Additivity Score: 3.15
  LHighest Single Agent (HSA) Score: 6.1

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Sorafenib

Disease Entry	ICD 11	Status	REF
Adenocarcinoma	2D40	Approved	[2]
Carcinoma	2A00-2F9Z	Approved	[2]
Clear cell renal carcinoma	N.A.	Approved	[2]
Lung cancer	2C25.0	Approved	[2]
Medullary thyroid gland carcinoma	N.A.	Approved	[2]
Non-small-cell lung cancer	2C25.Y	Approved	[2]
Renal cell carcinoma	2C90	Approved	[3]
Thyroid cancer	2D10	Approved	[2]
Hepatocellular carcinoma	2C12.02	Phase 3	[3]
Myelodysplastic syndrome	2A37	Phase 2	[3]

Sorafenib Interacts with 4 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Tyrosine-protein kinase Kit (KIT)	TTX41N9	KIT_HUMAN	Modulator	[10]
Platelet-derived growth factor receptor beta (PDGFRB)	TTI7421	PGFRB_HUMAN	Modulator	[10]
Epidermal growth factor receptor (EGFR)	TTGKNB4	EGFR_HUMAN	Inhibitor	[11]
Vascular endothelial growth factor receptor 2 (KDR)	TTUTJGQ	VGFR2_HUMAN	Modulator	[10]

Sorafenib Interacts with 7 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[12]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[13]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[14]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[15]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[16]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[15]
RalBP1-associated Eps domain-containing protein 2 (RALBP1)	DTYEM9B	REPS2_HUMAN	Substrate	[17]

Sorafenib Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[18]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[19]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[20]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[20]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[18]
UDP-glucuronosyltransferase 1A9 (UGT1A9)	DE85D2P	UD19_HUMAN	Metabolism	[21]

Sorafenib Interacts with 112 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C8 (CYP2C8)	OTHCWT42	CP2C8_HUMAN	Decreases Activity	[22]
ATP-binding cassette sub-family C member 2 (ABCC2)	OTJSIGV5	MRP2_HUMAN	Affects Response To Substance	[23]
Mast/stem cell growth factor receptor Kit (KIT)	OTHUY3VZ	KIT_HUMAN	Decreases Phosphorylation	[24]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Increases Expression	[25]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[26]
DNA damage-inducible transcript 4 protein (DDIT4)	OTHY8SY4	DDIT4_HUMAN	Increases Expression	[26]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[27]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Activity	[28]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Activity	[28]
Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (PIK3C2A)	OTFBU4GD	P3C2A_HUMAN	Decreases Expression	[5]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[5]
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Decreases Expression	[5]
GTPase NRas (NRAS)	OTVQ1DG3	RASN_HUMAN	Decreases Expression	[5]
Insulin-like growth factor 1 receptor (IGF1R)	OTXJIF13	IGF1R_HUMAN	Decreases Expression	[5]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[5]
Protein kinase C alpha type (PRKCA)	OT5UWNRD	KPCA_HUMAN	Decreases Expression	[5]
Cyclin-dependent kinase 2 (CDK2)	OTB5DYYZ	CDK2_HUMAN	Decreases Expression	[5]
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA)	OTTOMI8J	PK3CA_HUMAN	Decreases Expression	[5]
Serine/threonine-protein kinase mTOR (MTOR)	OTHH8KU7	MTOR_HUMAN	Decreases Expression	[5]
Cyclin-dependent kinase 9 (CDK9)	OT2B7OGB	CDK9_HUMAN	Decreases Expression	[5]
Growth factor receptor-bound protein 2 (GRB2)	OTOP7LTE	GRB2_HUMAN	Decreases Expression	[5]
E3 ubiquitin-protein ligase Mdm2 (MDM2)	OTOVXARF	MDM2_HUMAN	Increases Expression	[5]
Interferon regulatory factor 5 (IRF5)	OT8SIIAP	IRF5_HUMAN	Increases Expression	[5]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Decreases Expression	[5]
Serine/threonine-protein kinase PLK3 (PLK3)	OT19CT2Z	PLK3_HUMAN	Increases Expression	[5]
Serine/threonine-protein kinase PLK2 (PLK2)	OTKMJXJ8	PLK2_HUMAN	Increases Expression	[5]
Histone deacetylase 6 (HDAC6)	OT9W9MXQ	HDAC6_HUMAN	Decreases Expression	[5]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[26]
CASP8 and FADD-like apoptosis regulator (CFLAR)	OTX14BAS	CFLAR_HUMAN	Decreases Expression	[29]
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Decreases Expression	[30]
Zinc finger protein SNAI2 (SNAI2)	OT7Y8EJ2	SNAI2_HUMAN	Decreases Expression	[6]
E3 ubiquitin-protein ligase parkin (PRKN)	OTJBN41W	PRKN_HUMAN	Increases Ubiquitination	[31]
Growth arrest and DNA damage-inducible protein GADD45 beta (GADD45B)	OTL9I7LO	GA45B_HUMAN	Increases Expression	[32]
Protein phosphatase 1 regulatory subunit 15A (PPP1R15A)	OTYG179K	PR15A_HUMAN	Increases Expression	[7]
Growth arrest and DNA damage-inducible protein GADD45 gamma (GADD45G)	OT8V1J4M	GA45G_HUMAN	Increases Expression	[33]
Apoptosis-inducing factor 1, mitochondrial (AIFM1)	OTKPWB7Q	AIFM1_HUMAN	Affects Localization	[30]
Tyrosine-protein kinase ABL1 (ABL1)	OT09YVXH	ABL1_HUMAN	Decreases Activity	[34]
Urokinase-type plasminogen activator (PLAU)	OTX0QGKK	UROK_HUMAN	Decreases Expression	[35]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Activity	[36]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Secretion	[37]
RAF proto-oncogene serine/threonine-protein kinase (RAF1)	OT51LSFO	RAF1_HUMAN	Decreases Activity	[24]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Expression	[38]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases Expression	[32]
Tyrosine-protein kinase Lck (LCK)	OT883FG9	LCK_HUMAN	Decreases Phosphorylation	[39]
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Expression	[40]
Eukaryotic translation initiation factor 4E (EIF4E)	OTDAWNLA	IF4E_HUMAN	Decreases Phosphorylation	[30]
Proto-oncogene tyrosine-protein kinase receptor Ret (RET)	OTLU040A	RET_HUMAN	Decreases Activity	[41]
High mobility group protein B1 (HMGB1)	OT4B7CPF	HMGB1_HUMAN	Increases Expression	[37]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[42]
Breakpoint cluster region protein (BCR)	OTCN76C1	BCR_HUMAN	Decreases Activity	[34]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Decreases Activity	[22]
Cyclin-dependent kinase 4 (CDK4)	OT7EP05T	CDK4_HUMAN	Decreases Expression	[43]
Cadherin-1 (CDH1)	OTFJMXPM	CADH1_HUMAN	Increases Expression	[6]
Proto-oncogene tyrosine-protein kinase Src (SRC)	OTETYX40	SRC_HUMAN	Decreases Activity	[44]
Serine/threonine-protein kinase B-raf (BRAF)	OT7S81XQ	BRAF_HUMAN	Decreases Activity	[45]
Platelet-derived growth factor receptor alpha (PDGFRA)	OTDJXUCN	PGFRA_HUMAN	Decreases Phosphorylation	[46]
Cyclic AMP-dependent transcription factor ATF-4 (ATF4)	OTRFV19J	ATF4_HUMAN	Increases Expression	[26]
Ribosomal protein S6 kinase beta-1 (RPS6KB1)	OTAELNGX	KS6B1_HUMAN	Decreases Phosphorylation	[47]
Alanine aminotransferase 1 (GPT)	OTOXOA0Q	ALAT1_HUMAN	Increases Secretion	[48]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[49]
G1/S-specific cyclin-D2 (CCND2)	OTDULQF9	CCND2_HUMAN	Decreases Expression	[49]
G1/S-specific cyclin-D3 (CCND3)	OTNKPQ22	CCND3_HUMAN	Decreases Expression	[43]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Expression	[50]
Vascular endothelial growth factor receptor 2 (KDR)	OT15797V	VGFR2_HUMAN	Decreases Phosphorylation	[24]
Dual specificity mitogen-activated protein kinase kinase 2 (MAP2K2)	OTUE7Z91	MP2K2_HUMAN	Decreases Phosphorylation	[45]
Signal transducer and activator of transcription 3 (STAT3)	OTAAGKYZ	STAT3_HUMAN	Decreases Phosphorylation	[51]
Signal transducer and activator of transcription 5A (STAT5A)	OTBSJGN3	STA5A_HUMAN	Decreases Activity	[52]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Decreases Expression	[53]
Mitogen-activated protein kinase 8 (MAPK8)	OTEREYS5	MK08_HUMAN	Decreases Phosphorylation	[35]
Mitogen-activated protein kinase 9 (MAPK9)	OTCEVJ9E	MK09_HUMAN	Decreases Phosphorylation	[35]
Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4)	OTZPZX11	MP2K4_HUMAN	Decreases Phosphorylation	[35]
Crk-like protein (CRKL)	OTOYSD1R	CRKL_HUMAN	Decreases Phosphorylation	[34]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Increases Expression	[54]
CCAAT/enhancer-binding protein delta (CEBPD)	OTNBIPMY	CEBPD_HUMAN	Increases Expression	[33]
Glycogen synthase kinase-3 beta (GSK3B)	OTL3L14B	GSK3B_HUMAN	Increases Phosphorylation	[53]
Tumor necrosis factor ligand superfamily member 10 (TNFSF10)	OT4PXBTA	TNF10_HUMAN	Increases Response To Substance	[55]
Stanniocalcin-1 (STC1)	OTGVVXYF	STC1_HUMAN	Decreases Expression	[56]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[57]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[39]
Gasdermin-D (GSDMD)	OTH39BKI	GSDMD_HUMAN	Increases Expression	[37]
Sestrin-2 (SESN2)	OT889IXY	SESN2_HUMAN	Increases Expression	[58]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Phosphorylation	[59]
Cytochrome c (CYCS)	OTBFALJD	CYC_HUMAN	Affects Localization	[60]
Cyclin-dependent kinase 6 (CDK6)	OTR95N0X	CDK6_HUMAN	Decreases Expression	[43]
Dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1)	OT4Y9NQI	MP2K1_HUMAN	Decreases Phosphorylation	[45]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Cleavage	[30]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[30]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[61]
Baculoviral IAP repeat-containing protein 3 (BIRC3)	OT3E95KB	BIRC3_HUMAN	Decreases Expression	[62]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Decreases Expression	[47]
Eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1)	OTHBQVD5	4EBP1_HUMAN	Decreases Phosphorylation	[63]
Phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1)	OTXEE550	APR_HUMAN	Decreases Expression	[64]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Cleavage	[8]
Mitogen-activated protein kinase 14 (MAPK14)	OT5TCO3O	MK14_HUMAN	Decreases Expression	[65]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Decreases Expression	[30]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[66]
Bcl2-associated agonist of cell death (BAD)	OT63ERYM	BAD_HUMAN	Increases Expression	[8]
Docking protein 1 (DOK1)	OTGVRLW6	DOK1_HUMAN	Decreases Phosphorylation	[34]
Serine/threonine-protein kinase PINK1, mitochondrial (PINK1)	OT50NR57	PINK1_HUMAN	Increases Expression	[31]
Eukaryotic translation initiation factor 2A (EIF2A)	OTWXELQP	EIF2A_HUMAN	Increases Phosphorylation	[7]
Autophagy protein 5 (ATG5)	OT4T5SMS	ATG5_HUMAN	Increases Expression	[67]
Transcription factor SOX-17 (SOX17)	OT9H4WWE	SOX17_HUMAN	Decreases Localization	[68]
Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD)	OT37FKH0	CYLD_HUMAN	Increases Expression	[25]
Diablo IAP-binding mitochondrial protein (DIABLO)	OTHJ9MCZ	DBLOH_HUMAN	Affects Localization	[64]
Eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3)	OT0DZGY4	E2AK3_HUMAN	Increases Phosphorylation	[7]
E3 ubiquitin-protein ligase TRIM62 (TRIM62)	OT15YO6N	TRI62_HUMAN	Affects Response To Substance	[69]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Response To Substance	[30]
ATP-binding cassette sub-family C member 3 (ABCC3)	OTC3IJV4	MRP3_HUMAN	Affects Response To Substance	[23]
Hepatocyte growth factor (HGF)	OTGHUA23	HGF_HUMAN	Decreases Response To Substance	[70]
Multidrug resistance-associated protein 1 (ABCC1)	OTGUN89S	MRP1_HUMAN	Affects Response To Substance	[23]
Receptor-type tyrosine-protein kinase FLT3 (FLT3)	OTMSRYMK	FLT3_HUMAN	Increases Response To Substance	[59]
Na(+)/citrate cotransporter (SLC13A5)	OTPH1TA7	S13A5_HUMAN	Decreases Response To Substance	[71]

Indication(s) of Aminolevulinic Acid Hydrochloride

Disease Entry	ICD 11	Status	REF
Actinic keratosis	EK90.0	Approved	[4]

Aminolevulinic Acid Hydrochloride Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Protoporphyrinogen oxidase (PPOX)	TTNFMS9	PPOX_HUMAN	Modulator	[72]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Astrocytoma	DCQ8SUW	U251	Investigative	[1]
High grade ovarian serous adenocarcinoma	DCL1VUT	OVCAR-5	Investigative	[1]
Malignant melanoma	DC0EA7F	LOX IMVI	Investigative	[1]
Renal cell carcinoma	DCLNZWG	SN12C	Investigative	[1]
Invasive ductal carcinoma	DCYKREL	T-47D	Investigative	[73]

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] Sorafenib 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: 5711).
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] Novel carbocyclic curcumin analog CUR3d modulates genes involved in multiple apoptosis pathways in human hepatocellular carcinoma cells. Chem Biol Interact. 2015 Dec 5;242:107-22.
• [6] Destruxin B inhibits hepatocellular carcinoma cell growth through modulation of the Wnt/-catenin signaling pathway and epithelial-mesenchymal transition. Toxicol In Vitro. 2014 Jun;28(4):552-61. doi: 10.1016/j.tiv.2014.01.002. Epub 2014 Jan 13.
• [7] The kinase inhibitor sorafenib induces cell death through a process involving induction of endoplasmic reticulum stress. Mol Cell Biol. 2007 Aug;27(15):5499-513. doi: 10.1128/MCB.01080-06. Epub 2007 Jun 4.
• [8] Sorafenib induces apoptosis of AML cells via Bim-mediated activation of the intrinsic apoptotic pathway. Leukemia. 2008 Apr;22(4):808-18. doi: 10.1038/sj.leu.2405098. Epub 2008 Jan 17.
• [9] Ovatodiolide suppresses yes-associated protein 1-modulated cancer stem cell phenotypes in highly malignant hepatocellular carcinoma and sensitizes cancer cells to chemotherapy in vitro. Toxicol In Vitro. 2018 Sep;51:74-82. doi: 10.1016/j.tiv.2018.04.010. Epub 2018 Apr 24.
• [10] Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling.Mol Cancer Ther.2008 Oct;7(10):3129-40.
• [11] Nasopharyngeal carcinoma: Current treatment options and future directions. J Nasopharyng Carcinoma, 2014, 1(16): e16.
• [12] Multidrug resistance protein 2 implicates anticancer drug-resistance to sorafenib. Biol Pharm Bull. 2011;34(3):433-5.
• [13] Breast cancer resistance protein and P-glycoprotein limit sorafenib brain accumulation. Mol Cancer Ther. 2010 Feb;9(2):319-26.
• [14] Double-transduced MDCKII cells to study human P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) interplay in drug transport across the blood-brain barrier. Mol Pharm. 2011 Apr 4;8(2):571-82.
• [15] Contribution of OATP1B1 and OATP1B3 to the disposition of sorafenib and sorafenib-glucuronide. Clin Cancer Res. 2013 Mar 15;19(6):1458-66.
• [16] Upregulation of histone acetylation reverses organic anion transporter 2 repression and enhances 5-fluorouracil sensitivity in hepatocellular carcinoma
• [17] Rlip76 transports sunitinib and sorafenib and mediates drug resistance in kidney cancer. Int J Cancer. 2010 Mar 15;126(6):1327-38.
• [18] Interaction of sorafenib and cytochrome P450 isoenzymes in patients with advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. 2011 Nov;68(5):1111-8.
• [19] Ontogeny and sorafenib metabolism. Clin Cancer Res. 2012 Oct 15;18(20):5788-95.
• [20] Drug Interactions Flockhart Table
• [21] Pharmacokinetic interaction involving sorafenib and the calcium-channel blocker felodipine in a patient with hepatocellular carcinoma. Invest New Drugs. 2011 Dec;29(6):1511-4.
• [22] Differential inhibition of human CYP2C8 and molecular docking interactions elicited by sorafenib and its major N-oxide metabolite. Chem Biol Interact. 2021 Apr 1;338:109401. doi: 10.1016/j.cbi.2021.109401. Epub 2021 Feb 5.
• [23] The Enhanced metastatic potential of hepatocellular carcinoma (HCC) cells with sorafenib resistance. PLoS One. 2013 Nov 11;8(11):e78675. doi: 10.1371/journal.pone.0078675. eCollection 2013.
• [24] Sorafenib induces growth suppression in mouse models of gastrointestinal stromal tumor. Mol Cancer Ther. 2009 Jan;8(1):152-9. doi: 10.1158/1535-7163.MCT-08-0553.
• [25] Down-regulation of CYLD as a trigger for NF-B activation and a mechanism of apoptotic resistance in hepatocellular carcinoma cells. Int J Oncol. 2011 Jan;38(1):121-31.
• [26] Sorafenib induces apoptotic cell death in human non-small cell lung cancer cells by down-regulating mammalian target of rapamycin (mTOR)-dependent survivin expression. Biochem Pharmacol. 2011 Aug 1;82(3):216-26. doi: 10.1016/j.bcp.2011.04.011. Epub 2011 May 13.
• [27] Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol Sci. 2010 Dec; 118(2):485-500.
• [28] Differential effects of arsenic trioxide on chemosensitization in human hepatic tumor and stellate cell lines. BMC Cancer. 2012 Sep 10;12:402.
• [29] The multikinase inhibitor sorafenib potentiates TRAIL lethality in human leukemia cells in association with Mcl-1 and cFLIPL down-regulation. Cancer Res. 2007 Oct 1;67(19):9490-500. doi: 10.1158/0008-5472.CAN-07-0598.
• [30] Apoptosis induced by the kinase inhibitor BAY 43-9006 in human leukemia cells involves down-regulation of Mcl-1 through inhibition of translation. J Biol Chem. 2005 Oct 21;280(42):35217-27. doi: 10.1074/jbc.M506551200. Epub 2005 Aug 18.
• [31] Sorafenib targets the mitochondrial electron transport chain complexes and ATP synthase to activate the PINK1-Parkin pathway and modulate cellular drug response. J Biol Chem. 2017 Sep 8;292(36):15105-15120. doi: 10.1074/jbc.M117.783175. Epub 2017 Jul 3.
• [32] Induction of DNA damage-inducible gene GADD45beta contributes to sorafenib-induced apoptosis in hepatocellular carcinoma cells. Cancer Res. 2010 Nov 15;70(22):9309-18. doi: 10.1158/0008-5472.CAN-10-1033. Epub 2010 Nov 9.
• [33] Growth arrest DNA damage-inducible gene 45 gamma expression as a prognostic and predictive biomarker in hepatocellular carcinoma. Oncotarget. 2015 Sep 29;6(29):27953-65. doi: 10.18632/oncotarget.4446.
• [34] Sorafenib induces apoptosis specifically in cells expressing BCR/ABL by inhibiting its kinase activity to activate the intrinsic mitochondrial pathway. Cancer Res. 2009 May 1;69(9):3927-36. doi: 10.1158/0008-5472.CAN-08-2978. Epub 2009 Apr 14.
• [35] Synergistic antimetastatic effect of cotreatment with licochalcone A and sorafenib on human hepatocellular carcinoma cells through the inactivation of MKK4/JNK and uPA expression. Environ Toxicol. 2018 Dec;33(12):1237-1244. doi: 10.1002/tox.22630. Epub 2018 Sep 6.
• [36] Sorafenib inhibits transforming growth factor 1-mediated epithelial-mesenchymal transition and apoptosis in mouse hepatocytes. Hepatology. 2011 May;53(5):1708-18. doi: 10.1002/hep.24254.
• [37] Activation of inflammasomes by tyrosine kinase inhibitors of vascular endothelial growth factor receptor: Implications for VEGFR TKIs-induced immune related adverse events. Toxicol In Vitro. 2021 Mar;71:105063. doi: 10.1016/j.tiv.2020.105063. Epub 2020 Dec 1.
• [38] Sorafenib is an antagonist of the aryl hydrocarbon receptor. Toxicology. 2022 Mar 30;470:153118. doi: 10.1016/j.tox.2022.153118. Epub 2022 Feb 3.
• [39] Sorafenib induces cell death in chronic lymphocytic leukemia by translational downregulation of Mcl-1. Leukemia. 2011 May;25(5):838-47. doi: 10.1038/leu.2011.2. Epub 2011 Feb 4.
• [40] Cell cycle dependent and schedule-dependent antitumor effects of sorafenib combined with radiation. Cancer Res. 2007 Oct 1;67(19):9443-54. doi: 10.1158/0008-5472.CAN-07-1473.
• [41] Sorafenib functions to potently suppress RET tyrosine kinase activity by direct enzymatic inhibition and promoting RET lysosomal degradation independent of proteasomal targeting. J Biol Chem. 2007 Oct 5;282(40):29230-40. doi: 10.1074/jbc.M703461200. Epub 2007 Jul 30.
• [42] Synergistic activity of letrozole and sorafenib on breast cancer cells. Breast Cancer Res Treat. 2010 Nov;124(1):79-88. doi: 10.1007/s10549-009-0714-5. Epub 2010 Jan 7.
• [43] Coadministration of sorafenib with rottlerin potently inhibits cell proliferation and migration in human malignant glioma cells. J Pharmacol Exp Ther. 2006 Dec;319(3):1070-80. doi: 10.1124/jpet.106.108621. Epub 2006 Sep 7.
• [44] Sorafenib induces apoptosis in HL60 cells by inhibiting Src kinase-mediated STAT3 phosphorylation. Anticancer Drugs. 2011 Jan;22(1):79-88. doi: 10.1097/CAD.0b013e32833f44fd.
• [45] Rap1/B-Raf signaling is activated in neuroendocrine tumors of the digestive tract and Raf kinase inhibition constitutes a putative therapeutic target. Neuroendocrinology. 2007;85(1):45-53. doi: 10.1159/000100508. Epub 2007 Mar 5.
• [46] Potent activity of ponatinib (AP24534) in models of FLT3-driven acute myeloid leukemia and other hematologic malignancies. Mol Cancer Ther. 2011 Jun;10(6):1028-35. doi: 10.1158/1535-7163.MCT-10-1044. Epub 2011 Apr 11.
• [47] 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.
• [48] Cytotoxicity of 34 FDA approved small-molecule kinase inhibitors in primary rat and human hepatocytes. Toxicol Lett. 2018 Jul;291:138-148. doi: 10.1016/j.toxlet.2018.04.010. Epub 2018 Apr 12.
• [49] Sorafenib inhibits signal transducer and activator of transcription 3 signaling associated with growth arrest and apoptosis of medulloblastomas. Mol Cancer Ther. 2008 Nov;7(11):3519-26. doi: 10.1158/1535-7163.MCT-08-0138.
• [50] Therapeutic targeting of hepatocellular carcinoma cells with antrocinol, a novel, dual-specificity, small-molecule inhibitor of the KRAS and ERK oncogenic signaling pathways. Chem Biol Interact. 2023 Jan 25;370:110329. doi: 10.1016/j.cbi.2022.110329. Epub 2022 Dec 22.
• [51] Sorafenib derivatives induce apoptosis through inhibition of STAT3 independent of Raf. Eur J Med Chem. 2011 Jul;46(7):2845-51. doi: 10.1016/j.ejmech.2011.04.007. Epub 2011 Apr 14.
• [52] The multikinase inhibitor sorafenib induces apoptosis in highly imatinib mesylate-resistant bcr/abl+ human leukemia cells in association with signal transducer and activator of transcription 5 inhibition and myeloid cell leukemia-1 down-regulation. Mol Pharmacol. 2007 Sep;72(3):788-95. doi: 10.1124/mol.106.033308. Epub 2007 Jun 26.
• [53] Arsenic trioxide potentiates the anti-cancer activities of sorafenib against hepatocellular carcinoma by inhibiting Akt activation. Tumour Biol. 2015 Apr;36(4):2323-34. doi: 10.1007/s13277-014-2839-3. Epub 2014 Nov 22.
• [54] Proliferation and survival molecules implicated in the inhibition of BRAF pathway in thyroid cancer cells harbouring different genetic mutations. BMC Cancer. 2009 Oct 31;9:387. doi: 10.1186/1471-2407-9-387.
• [55] The multikinase inhibitor Sorafenib induces apoptosis and sensitises endometrial cancer cells to TRAIL by different mechanisms. Eur J Cancer. 2010 Mar;46(4):836-50. doi: 10.1016/j.ejca.2009.12.025. Epub 2010 Jan 12.
• [56] Downregulation of stanniocalcin 1 is responsible for sorafenib-induced cardiotoxicity. Toxicol Sci. 2015 Feb;143(2):374-84. doi: 10.1093/toxsci/kfu235. Epub 2014 Nov 3.
• [57] Sorafenib induces preferential apoptotic killing of a drug- and radio-resistant Hep G2 cells through a mitochondria-dependent oxidative stress mechanism. Cancer Biol Ther. 2009 Oct;8(20):1904-13. doi: 10.4161/cbt.8.20.9436. Epub 2009 Oct 6.
• [58] Protective effect of sestrin2 against iron overload and ferroptosis-induced liver injury. Toxicol Appl Pharmacol. 2019 Sep 15;379:114665. doi: 10.1016/j.taap.2019.114665. Epub 2019 Jul 16.
• [59] Mechanisms of apoptosis induction by simultaneous inhibition of PI3K and FLT3-ITD in AML cells in the hypoxic bone marrow microenvironment. Cancer Lett. 2013 Feb 1;329(1):45-58. doi: 10.1016/j.canlet.2012.09.020. Epub 2012 Oct 2.
• [60] The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006. Oncogene. 2005 Oct 20;24(46):6861-9. doi: 10.1038/sj.onc.1208841.
• [61] Why are most phospholipidosis inducers also hERG blockers?. Arch Toxicol. 2017 Dec;91(12):3885-3895. doi: 10.1007/s00204-017-1995-9. Epub 2017 May 27.
• [62] The multikinase inhibitor sorafenib induces caspase-dependent apoptosis in PC-3 prostate cancer cells. Asian J Androl. 2010 Jul;12(4):527-34. doi: 10.1038/aja.2010.21. Epub 2010 May 17.
• [63] Synergistic inhibition of human melanoma proliferation by combination treatment with B-Raf inhibitor BAY43-9006 and mTOR inhibitor Rapamycin. J Transl Med. 2005 Oct 28;3:39. doi: 10.1186/1479-5876-3-39.
• [64] GSK-3beta inhibition enhances sorafenib-induced apoptosis in melanoma cell lines. J Biol Chem. 2008 Jan 11;283(2):726-32. doi: 10.1074/jbc.M705343200. Epub 2007 Nov 8.
• [65] Cytotoxic synergy between the multikinase inhibitor sorafenib and the proteasome inhibitor bortezomib in vitro: induction of apoptosis through Akt and c-Jun NH2-terminal kinase pathways. Mol Cancer Ther. 2006 Sep;5(9):2378-87. doi: 10.1158/1535-7163.MCT-06-0235.
• [66] 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.
• [67] Vorinostat and sorafenib increase ER stress, autophagy and apoptosis via ceramide-dependent CD95 and PERK activation. Cancer Biol Ther. 2008 Oct;7(10):1648-62. doi: 10.4161/cbt.7.10.6623. Epub 2008 Oct 12.
• [68] A high-throughput screen for teratogens using human pluripotent stem cells. Toxicol Sci. 2014 Jan;137(1):76-90. doi: 10.1093/toxsci/kft239. Epub 2013 Oct 23.
• [69] TRIM62 silencing represses the proliferation and invasion and increases the chemosensitivity of hepatocellular carcinoma cells by affecting the NF-B pathway. Toxicol Appl Pharmacol. 2022 Jun 15;445:116035. doi: 10.1016/j.taap.2022.116035. Epub 2022 Apr 23.
• [70] Diospyros kaki leaves inhibit HGF/Met signaling-mediated EMT and stemness features in hepatocellular carcinoma. Food Chem Toxicol. 2020 Aug;142:111475. doi: 10.1016/j.fct.2020.111475. Epub 2020 Jun 6.
• [71] Comparative proteomic analysis of SLC13A5 knockdown reveals elevated ketogenesis and enhanced cellular toxic response to chemotherapeutic agents in HepG2 cells. Toxicol Appl Pharmacol. 2020 Sep 1;402:115117. doi: 10.1016/j.taap.2020.115117. Epub 2020 Jul 4.
• [72] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [73] Biologically active neutrophil chemokine pattern in tonsillitis.Clin Exp Immunol. 2004 Mar;135(3):511-8. doi: 10.1111/j.1365-2249.2003.02390.x.