Ferroptosis-centered Drug Response Information

General Information of the Drug (ID: ferrodrug0038)
Name
Sorafenib
Synonyms
Sorafenib; 284461-73-0; Nexavar; BAY 43-9006; sorafenibum; 4-(4-(3-(4-CHLORO-3-(TRIFLUOROMETHYL)PHENYL)UREIDO)PHENOXY)-N-METHYLPICOLINAMIDE; 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenoxy]-N-methylpyridine-2-carboxamide; Sorafenib free base; 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide; UNII-9ZOQ3TZI87; N-(4-Chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea; 100012-18-8; 9ZOQ3TZI87; BAY-43-9006; 4-(4-((((4-Chloro-3-(trifluoromethyl)phenyl)amino)carbonyl)amino)phenoxy)-N-methyl-2-pyridinecarboxamide; DTXSID7041128; CHEBI:50924; HSDB 8173; 284461-73-0 (free base); MFCD06411450; BAY43-9006; CHEMBL1336; 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methyl-pyridine-2-carboxamide; 2-Pyridinecarboxamide, 4-(4-((((4-chloro-3-(trifluoromethyl)phenyl)amino)carbonyl)amino)phenoxy)-N-methyl-; 4-{4-[({[4-CHLORO-3-(TRIFLUOROMETHYL)PHENYL]AMINO}CARBONYL)AMINO]PHENOXY}-N-METHYLPYRIDINE-2-CARBOXAMIDE; EC 608-209-4; BAY-439006; Sorafenib [INN]; 4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide; Sorafenib (Nexavar); SORAFENIB (MART.); SORAFENIB [MART.]; 4-(4-{3-(4-Chloro-3-(trifluoromethyl)phenyl)ureido}phenoxy)-N(sup 2)-methylpyridine-2-carboxamide; Donafenib (Sorafenib D3); 2-Pyridinecarboxamide, 4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-; 4-(4-(3-(4-CHLORO-3-(TRIFLUOROMETHYL)PHENYL)UREIDO)PHENOXY)-N(SUP 2)-METHYLPYRIDINE-2-CARBOXAMIDE; BAX; NSC-724772; NCGC00167488-01; Sorafenib [USAN:INN:BAN]; SR-00000000529; 1uwh; 3gcs; 3heg; 4asd; Hit compound, 8; Sorafenib, 4; 4-(4-(((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)amino)phenoxy)-N-methylpyridine-2-carboxamide; 4-[4-[[[[4-Chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide; BAY 43-9006; N-[4-Chloro-3-(trifluoromethyl)phenyl]-N'-[4-[2-(N-methylcarbamoyl)-4-pyridyloxy]phenyl]urea; Nevaxar; Sorafenib; Manganese(4+), chloro[[4,4',4'',4'''-(21H,23H-porphine-5,10,15,20-tetrayl-kappaN21,kappaN22,kappaN23,kappaN24)tetrakis[1-methylpyridiniumato]](2-)]-, chloride (1:4), (SP-5-12)-; BAY 439006; 4-(4-(3-(4-chloro-3-trifluoromethylphenyl)ureido)phenoxy)pyridine-2-carboxyllic acid methyamide-4-methylbenzenesulfonate; Kinome_766; SORAFENIB BASE; SORAFENIB [MI]; Sorafenib (USAN/INN); SORAFENIB [USAN]; Nexavar (TN) (Bayer); sorafenib tosilate hydrate; SORAFENIB [VANDF]; SCHEMBL8218; SORAFENIB [WHO-DD]; SORAFENIB [EMA EPAR]; BAY 43-9006; Sorafenib; cid_216239; GTPL5711; DTXCID5021128; BDBM16673; L01XE05; BCPP000064; HMS2043A18; HMS3244A15; HMS3244A16; HMS3244B15; HMS3656N20; K00597a; BCP01767; BCP34023; EX-A2894; BAY439006; NSC747971; NSC800934; s7397; STK627350; AKOS005560229; AC-1674; CCG-269400; CS-1590; DB00398; NSC-747971; NSC-800934; PB14443; SB19942; SF-0529; BAY-43-0006; Sorafenib free base (BAY-43-9006); NCGC00167488-02; NCGC00167488-03; NCGC00167488-04; NCGC00167488-05; NCGC00167488-07; NCGC00167488-14; 4(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N(sup 2)-methylpyridine-2-carboxamide; BS164413; HY-10201; N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcar bamoyl)-4-pyridyloxy)phenyl)urea; SY009239; PA-216239; AM20090614; FT-0650736; FT-0674632; SW202562-4; BA4 43 9006; D08524; EN300-120647; AB00933189-05; AB00933189-06; AB00933189_08; A819449; Q421136; Q-201728; SR-00000000529-1; BRD-K23984367-001-01-8; Z89277543; BAY 439006; BAY439006; BAY-439006; Sorafenib (D3); CM-4307; CM 4307; CM4307;Bay 43-9006 (D3); 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl) ureido) phenoxy)-N-methylpicolinamide; 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl) ureido)phenoxy)-N-methylpicolinamide; N-(3-trifluoromethyl-4-chlorophenyl)-N'-(4-(2-methylcarbamoyl pyridin-4-yl)oxyphenyl)urea; 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)- N-methylpyridine-2-carboxamide; 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide; 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methyl-picolinamide;tosylic acid; 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)-amino]phenoxy}-N-methylpyridine-2-carboxamide; 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methyl-pyridine-2-carboxamide; Manganese(4+), chloro[[4,4',4'',4'''-(21H,23H-porphine-5,10,15,20-tetrayl-N21,N22,N23,N24)tetrakis[1-methylpyridiniumato]](2-)]-, chloride (1:4), (SP-5-12)-; N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea

    Click to Show/Hide
Structure
Formula
C21H16ClF3N4O3
IUPAC Name
4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide
Canonical SMILES
CNC(=O)C1=NC=CC(=C1)OC2=CC=C(C=C2)NC(=O)NC3=CC(=C(C=C3)Cl)C(F)(F)F
InChI
InChI=1S/C21H16ClF3N4O3/c1-26-19(30)18-11-15(8-9-27-18)32-14-5-2-12(3-6-14)28-20(31)29-13-4-7-17(22)16(10-13)21(23,24)25/h2-11H,1H3,(H,26,30)(H2,28,29,31)
InChIKey
MLDQJTXFUGDVEO-UHFFFAOYSA-N
PubChem CID
216239
Full List of Ferroptosis Target Related to This Drug
Phospholipid hydroperoxide glutathione peroxidase (GPX4)
 Target Info 
In total 2 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [1]
Target for Ferroptosis Suppressor
Responsed Disease Hepatocellular carcinoma ICD-11: 2C12
 Disease Info 
Responsed Regulator Protein lifeguard 4 (TMBIM4) Suppressor
 Regulator Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
Huh-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0336
SMMC-7721 cells Endocervical adenocarcinoma Homo sapiens CVCL_0534
PLC/PRF/5 cells Hepatocellular carcinoma Homo sapiens CVCL_0485
In Vivo Model
To generate murine subcutaneous tumours, 1 x 107 control shRNA or S1R-knockdown Huh7 cells in 200 uL of PBS were injected subcutaneously to the right of the dorsal midline. At day seven, the mice were randomly divided into groups and treated with sorafenib (10 mg/kg/intraperitoneal injection (i.p.), once every other day) for 2 weeks. On day 28, tumours were removed.

    Click to Show/Hide
Response regulation S1R (TMBIM4) protects hepatocellular carcinoma cells against sorafenib and subsequent ferroptosis. Inhibition of S1R by RNAi and antagonists markedly increased the anticancer activity of sorafenib by modulating the expression of GPX4, iron metabolism and ROS.
Experiment 2 Reporting the Ferroptosis-centered Drug Act on This Target [2]
Target for Ferroptosis Suppressor
Responsed Disease Hepatocellular carcinoma ICD-11: 2C12
 Disease Info 
Responsed Regulator HCG18 (IncRNA) Suppressor
 Regulator Info 
Pathway Response Ferroptosis hsa04216
Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
Cell apoptosis
Cell proliferation
In Vitro Model SK-HEP-1 cells Liver and intrahepatic bile duct epithelial neoplasm Homo sapiens CVCL_0525
Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
HCCLM3 cells Adult hepatocellular carcinoma Homo sapiens CVCL_6832
Huh-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0336
L-02 cells Endocervical adenocarcinoma Homo sapiens CVCL_6926
In Vivo Model
BALB/c nude mice (4-6 weeks old) from Beijing Vital River Laboratory Animal Technology (Beijing, China) were reared in a standard laboratory with free access to food and water. Lentivirus LV-sh-NC and LV-sh-HCG18 were from GenePharma (Shanghai, China). In order to establish subcutaneous xenograft tumor models, Huh7-SR cells were infected with lentivirus LV-sh-NC or LV-sh-HCG18 and then resuspended in PBS at 5 x 105/mL. Totally 100 uL cells were subcutaneously injected into the right dorsal area of each nude mouse. When the tumor volume reached 150 mm3, sorafenib (10 mg/kg) was orally administered to nude mice once a day to the end. Tumor volume (V) was calculated: V = 0.5 x L x W2, where L and W were defined as tumor length (L) and width (W). After 28 days of cell injection, the nude mice were euthanized by intraperitoneal injection of excessive pentobarbital sodium (100 mg/kg).

    Click to Show/Hide
Response regulation HCG18 sponged miR-450b-5p to regulate GPX4. Collectively, Silencing HCG18 inhibits GPX4 by binding to miR-450b-5p, promotes GPX4-inhibited ferroptosis, and averts sorafenib resistance in hepatocellular carcinoma (HCC). Silencing HCG18 inhibited cell proliferation, promoted apoptosis, and impaired sorafenib resistance.
Nuclear receptor coactivator 4 (NCOA4)
 Target Info 
In total 4 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [3]
Target for Ferroptosis Driver
Responsed Disease Liver fibrosis ICD-11: DB93
 Disease Info 
Responsed Regulator mRNA decay activator protein ZFP36 (ZFP36) Suppressor
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model hHSCs (Human hepatic stellate cells)
In Vivo Model
Fifty-six 8-week-old male C57BL/6 mice were obtained from the Experimental Animal Center of Yangzhou University (Yangzhou, China). Controls underwent a sham operation that consisted of exposure, but not ligation, of the common bile duct. Erastin (30 mg/kg, once every other day) and sorafenib (10 mg/kg, once every other day) were suspended in sterile phosphate-buffered saline (PBS; Sigma, P5368) and given by intraperitoneal injection for 2 weeks after the BDL operation. VA-Lip-control-vector and VA-Lip-Zfp36-plasmid (0.75 mg/kg) were administered intravenously 3 times a week for 2 weeks after the BDL operation.

    Click to Show/Hide
Response regulation Sorafenib monotherapy led to ZFP36 downregulation, ferritinophagy activation, and ferroptosis induction in human HSCs. ZFP36 plasmid markedly upregulated, whereas FBXW7 plasmid apparently downregulaed, ferritin and NCOA4 expression in sorafenib-treated HSC-LX2 cells. The study identified ZFP36-autophagy-dependent ferroptosis as a potential target for the treatment of liver fibrosis.
Experiment 2 Reporting the Ferroptosis-centered Drug Act on This Target [3]
Target for Ferroptosis Driver
Responsed Disease Liver fibrosis ICD-11: DB93
 Disease Info 
Responsed Regulator Autophagy-related protein 16-1 Driver
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model hHSCs (Human hepatic stellate cells)
In Vivo Model
Fifty-six 8-week-old male C57BL/6 mice were obtained from the Experimental Animal Center of Yangzhou University (Yangzhou, China). Controls underwent a sham operation that consisted of exposure, but not ligation, of the common bile duct. Erastin (30 mg/kg, once every other day) and sorafenib (10 mg/kg, once every other day) were suspended in sterile phosphate-buffered saline (PBS; Sigma, P5368) and given by intraperitoneal injection for 2 weeks after the BDL operation. VA-Lip-control-vector and VA-Lip-Zfp36-plasmid (0.75 mg/kg) were administered intravenously 3 times a week for 2 weeks after the BDL operation.

    Click to Show/Hide
Response regulation Sorafenib monotherapy led to ZFP36 downregulation, ferritinophagy activation, and ferroptosis induction in human HSCs. ATG16L1 plasmid eliminated the inhibitory action of ZFP36 plasmid on ferroptosis, and FBXW7 plasmid enhanced the effect of ATG16L1 plasmid on autophagy. ZFP36 plasmid markedly upregulated, whereas FBXW7 plasmid apparently downregulaed, ferritin and NCOA4 expression in sorafenib-treated HSC-LX2 cells. The study identified ZFP36-autophagy-dependent ferroptosis as a potential target for the treatment of liver fibrosis.
Experiment 3 Reporting the Ferroptosis-centered Drug Act on This Target [3]
Target for Ferroptosis Driver
Responsed Disease Liver fibrosis ICD-11: DB93
 Disease Info 
Responsed Regulator F-box/WD repeat-containing protein 7 (FBXW7) Driver
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model hHSCs (Human hepatic stellate cells)
In Vivo Model
Fifty-six 8-week-old male C57BL/6 mice were obtained from the Experimental Animal Center of Yangzhou University (Yangzhou, China). Controls underwent a sham operation that consisted of exposure, but not ligation, of the common bile duct. Erastin (30 mg/kg, once every other day) and sorafenib (10 mg/kg, once every other day) were suspended in sterile phosphate-buffered saline (PBS; Sigma, P5368) and given by intraperitoneal injection for 2 weeks after the BDL operation. VA-Lip-control-vector and VA-Lip-Zfp36-plasmid (0.75 mg/kg) were administered intravenously 3 times a week for 2 weeks after the BDL operation.

    Click to Show/Hide
Response regulation Sorafenib monotherapy led to ZFP36 downregulation, ferritinophagy activation, and ferroptosis induction in human HSCs. ZFP36 plasmid markedly upregulated, whereas FBXW7 plasmid apparently downregulaed, ferritin and NCOA4 expression in sorafenib-treated HSC-LX2 cells. The study identified ZFP36-autophagy-dependent ferroptosis as a potential target for the treatment of liver fibrosis.
Experiment 4 Reporting the Ferroptosis-centered Drug Act on This Target [4]
Target for Ferroptosis Driver
Responsed Disease Liver fibrosis ICD-11: DB93
 Disease Info 
Responsed Regulator ELAV-like protein 1 (ELAVL1) Driver
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Autophagy hsa04140
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model hHSCs (Human hepatic stellate cells)
In Vivo Model
Eight-week-old male C57BL/6 mice were purchased from the Experimental Animal Center of Yangzhou University (Yangzhou, China). Sorafenib (10 mg/kg, once every other day) was suspended in sterile phosphate-buffered saline (PBS; Sigma, P5368) and given by intraperitoneal injection for 2 weeks after the BDL operation. The livers were collected 2 weeks after surgery under general anesthesia.

    Click to Show/Hide
Response regulation Sorafenib treatment remarkably upregulated NCOA4 expression, and 3 critical events including ELAVL1 upregulation, ferritinophagy activation, and ferroptosis induction occur in primary human HSCs from fibrotic patients receiving sorafenib monotherapy. ELAVL1 is a potential target for the treatment of liver fibrosis.
Nuclear factor erythroid 2-related factor 2 (NFE2L2)
 Target Info 
In total 2 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [5]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Hepatocellular carcinoma ICD-11: 2C12
 Disease Info 
Responsed Regulator Sequestosome-1 (SQSTM1) Suppressor
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
Hepa 1-6 cells Hepatocellular carcinoma Mus musculus CVCL_0327
Hep 3B2.1-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0326
Hep 3B2.1-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0326
In Vivo Model
To generate murine subcutaneous tumors, 1 x 106 Hepa16 cells in control shRNA or NRF2 knockdown cells in 200 ul phosphate buffered saline were injected subcutaneously to the right of the dorsal midline in C57BL/6 mice. Once the tumors reached 80-100 mm3 at day seven, mice were randomly allocated into groups and treated with erastin (30 mg/kg intraperitoneal injection [i.p.], twice every other day) and sorafenib (10 mg/kg i.p., once every other day) for two weeks.

    Click to Show/Hide
Response regulation Upon exposure to ferroptosis-inducing compounds (e.g., erastin, sorafenib, and buthionine sulfoximine), p62 (SQSTM1) expression prevented NRF2 degradation and enhanced subsequent NRF2 nuclear accumulation through inactivation of Kelch-like ECH-associated protein 1. The status of NRF2 is a key factor that determines the therapeutic response to ferroptosis-targeted therapies in hepatocellular carcinoma cells.
Experiment 2 Reporting the Ferroptosis-centered Drug Act on This Target [8]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Lung cancer ICD-11: 2C25
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
NCI-H1299 cells Lung large cell carcinoma Homo sapiens CVCL_0060
In Vivo Model
A total of 60 BALB/c-nu/nu nude mice (male; age, 4-6 weeks; weight, 16-22 g) were obtained from the Shanghai Laboratory Animal Co., Ltd. N5CP cells (5 x 106) were suspended in 200 ul DMEM and Matrigel mixture at a ratio of 1:1. Subsequently, the mixture was injected subcutaneously into the upper right flank of 20 nude mice. After 10 days, the mice were randomly divided into four groups and were treated with CDDP (5 mg/kg/2 days), erastin (10 mg/kg/2 days), sorafenib (10 mg/kg/2 days) or PBS by intraperitoneal injection. Two days after the third injection, the mice were sacrificed and tumours were carefully removed. For the combination experiment, CDDP (1 mg/kg) and erastin (5 mg/kg) or sorafenib (3 mg/kg) were also injected three times.

    Click to Show/Hide
Response regulation The potential mechanism by which sorafenib and erastin induced ferroptosis in cisplatin (CDDP)-resistant non-small cell lung cancer (NSCLC) cells may be associated with inhibition of the expression of the Nrf2 downstream target gene xCT.
Long-chain-fatty-acid--CoA ligase 4 (ACSL4)
 Target Info 
In total 2 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [6]
Target for Ferroptosis Driver
Responsed Disease Hepatocellular carcinoma ICD-11: 2C12
 Disease Info 
Responsed Regulator Protein C-ets-1 (ETS1) Suppressor
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model MHCC97-L cells Hepatocellular carcinoma Homo sapiens CVCL_4973
PLC/PRF/5 cells Hepatocellular carcinoma Homo sapiens CVCL_0485
HEK293 FT cells Normal Homo sapiens CVCL_6911
In Vivo Model
Parental MHCC97L cells (2 x 106 cells/mouse) were subcutaneously injected into the 4-to-5-week-old NOD-SCID mice. When the tumours reached a volume of around 50-100 mm3 (calculated by the formula 4/3(D/2)(d/2)2, where D and d represent the minor and major axis of the tumour, respectively), the maximum tolerated dose of sorafenib (50 mg/kg) was given to the mice by oral gavage daily until the drug resistance occurred, denoted as the drug resistant group. For the control, the wild type group was treated with the vehicle (0.5% CMC-Na). The tumour size and body weight were measured every 3 days.

    Click to Show/Hide
Response regulation Sorafenib treatment triggered ferroptosis via lipid ROS production and chelatable iron accumulation. The ETS1 upregulated by sorafenib was a key transcription factor of miR-23a-3p that directly enhanced miR-23a-3p expression. MiR-23a-3p recognized and bound to ACSL4 3UTR to limit lipid ROS production, thus attenuating sorafenib-induced ferroptotic cell death in hepatocellular carcinoma.
Experiment 2 Reporting the Ferroptosis-centered Drug Act on This Target [6]
Target for Ferroptosis Driver
Responsed Disease Hepatocellular carcinoma ICD-11: 2C12
 Disease Info 
Responsed Regulator hsa-miR-23a-3p (miRNA) Suppressor
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model MHCC97-L cells Hepatocellular carcinoma Homo sapiens CVCL_4973
PLC/PRF/5 cells Hepatocellular carcinoma Homo sapiens CVCL_0485
HEK293 FT cells Normal Homo sapiens CVCL_6911
In Vivo Model
Parental MHCC97L cells (2 x 106 cells/mouse) were subcutaneously injected into the 4-to-5-week-old NOD-SCID mice. When the tumours reached a volume of around 50-100 mm3 (calculated by the formula 4/3(D/2)(d/2)2, where D and d represent the minor and major axis of the tumour, respectively), the maximum tolerated dose of sorafenib (50 mg/kg) was given to the mice by oral gavage daily until the drug resistance occurred, denoted as the drug resistant group. For the control, the wild type group was treated with the vehicle (0.5% CMC-Na). The tumour size and body weight were measured every 3 days.

    Click to Show/Hide
Response regulation Sorafenib treatment triggered ferroptosis via lipid ROS production and chelatable iron accumulation. The ETS1 upregulated by sorafenib was a key transcription factor of miR-23a-3p that directly enhanced miR-23a-3p expression. MiR-23a-3p recognized and bound to ACSL4 3UTR to limit lipid ROS production, thus attenuating sorafenib-induced ferroptotic cell death in hepatocellular carcinoma.
Unspecific Target
In total 1 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [7]
Responsed Disease Hepatocellular carcinoma ICD-11: 2C12
 Disease Info 
Responsed Regulator Ragulator complex protein LAMTOR5 (LAMTOR5) Suppressor
 Regulator Info 
Pathway Response Glutathione metabolism hsa00480
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model L-02 cells Endocervical adenocarcinoma Homo sapiens CVCL_6926
Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
Hep 3B2.1-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0326
SMMC-7721 cells Endocervical adenocarcinoma Homo sapiens CVCL_0534
Huh-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0336
BEL-7402 cells Endocervical adenocarcinoma Homo sapiens CVCL_5492
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
Six-week-old male BALB/c athymic nude mice were purchased from the Experimental Animal Center of Peking (Beijing, China). Stable cells (5 x 106) were seeded into the right flanks of the mice. After the xenografts had grown to 200 mm3, saline as a vehicle or sorafenib (30 mg/kg) was administered by gavage every day, and the mice were euthanized by the cervical dislocation method five weeks later. Before sacrifice, the tumor sizes and body weights were measured twice per week. The tumor volume (V) was calculated as follows: (L x W2)/2 (length, L, and width, W). The xenografts were excised and further assessed.

    Click to Show/Hide
Response regulation Sorafenib decreased HBXIP expression, and overexpression of HBXIP blocked sorafenib-induced hepatocellular carcinoma cell death. Regarding the molecular mechanism, HBXIP transcriptionally induced the expression of stearoyl-CoA desaturase (SCD) via coactivating the transcriptional factor ZNF263, resulting in the accumulation of free fatty acids and suppression of ferroptosis.
Stearoyl-CoA desaturase (SCD)
 Target Info 
In total 1 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [7]
Target for Ferroptosis Suppressor
Responsed Disease Hepatocellular carcinoma ICD-11: 2C12
 Disease Info 
Pathway Response Glutathione metabolism hsa00480
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model L-02 cells Endocervical adenocarcinoma Homo sapiens CVCL_6926
Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
Hep 3B2.1-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0326
SMMC-7721 cells Endocervical adenocarcinoma Homo sapiens CVCL_0534
Huh-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0336
BEL-7402 cells Endocervical adenocarcinoma Homo sapiens CVCL_5492
HEK-293T cells Normal Homo sapiens CVCL_0063
In Vivo Model
Six-week-old male BALB/c athymic nude mice were purchased from the Experimental Animal Center of Peking (Beijing, China). Stable cells (5 x 106) were seeded into the right flanks of the mice. After the xenografts had grown to 200 mm3, saline as a vehicle or sorafenib (30 mg/kg) was administered by gavage every day, and the mice were euthanized by the cervical dislocation method five weeks later. Before sacrifice, the tumor sizes and body weights were measured twice per week. The tumor volume (V) was calculated as follows: (L x W2)/2 (length, L, and width, W). The xenografts were excised and further assessed.

    Click to Show/Hide
Response regulation Sorafenib decreased HBXIP expression, and overexpression of HBXIP blocked sorafenib-induced Hepatocellular carcinoma cell death. Regarding the molecular mechanism, HBXIP transcriptionally induced the expression of stearoyl-CoA desaturase (SCD) via coactivating the transcriptional factor ZNF263, resulting in the accumulation of free fatty acids and suppression of ferroptosis.
Cystine/glutamate transporter (SLC7A11)
 Target Info 
In total 1 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [9]
Target for Ferroptosis Suppressor
Responsed Disease Hepatocellular carcinoma ICD-11: 2C12
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model Hep-G2 cells Hepatoblastoma Homo sapiens CVCL_0027
SNU-182 cells Adult hepatocellular carcinoma Homo sapiens CVCL_0090
SNU-449 cells Adult hepatocellular carcinoma Homo sapiens CVCL_0454
In Vivo Model
A total of 20 male Balb/c nude mice aged 6-8 weeks were purchased from Hunan SJA Laboratory Animal Co., Ltd. (Changsha, China). Five million Huh7 cells were inoculated into the right flanks of the mice. When the tumor size reached 80-100 mm3, the mice were randomly divided into four groups and administered artesunate (30 mg/kg mouse weight) alone, sorafenib (20 mg/kg mouse weight) alone, a combination of artesunate and sorafenib, or the same volume of PBS by gavage every other day.

    Click to Show/Hide
Response regulation Sorafenib at low dose mainly caused oxidative stress through mitochondrial impairments and SLC7A11-invovled glutathione depletion. Artesunate-induced lysosome activation synergized with sorafenib-mediated pro-oxidative effects by promoting sequential reactions including lysosomal cathepsin B/L activation, ferritin degradation, lipid peroxidation, and consequent ferroptosis. Taken together, artesunate could be repurposed to sensitize sorafenib in hepatocellular carcinoma treatment.
References
Ref 1 Sigma-1 receptor protects against ferroptosis in hepatocellular carcinoma cells. J Cell Mol Med. 2019 Nov;23(11):7349-7359. doi: 10.1111/jcmm.14594. Epub 2019 Sep 10.
Ref 2 Silencing lncRNA HCG18 regulates GPX4-inhibited ferroptosis by adsorbing miR-450b-5p to avert sorafenib resistance in hepatocellular carcinoma. Hum Exp Toxicol. 2023 Jan-Dec;42:9603271221142818. doi: 10.1177/09603271221142818.
Ref 3 RNA-binding protein ZFP36/TTP protects against ferroptosis by regulating autophagy signaling pathway in hepatic stellate cells. Autophagy. 2020 Aug;16(8):1482-1505. doi: 10.1080/15548627.2019.1687985. Epub 2019 Nov 11.
Ref 4 Activation of ferritinophagy is required for the RNA-binding protein ELAVL1/HuR to regulate ferroptosis in hepatic stellate cells. Autophagy. 2018;14(12):2083-2103. doi: 10.1080/15548627.2018.1503146. Epub 2018 Aug 21.
Ref 5 Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology. 2016 Jan;63(1):173-84. doi: 10.1002/hep.28251. Epub 2015 Nov 26.
Ref 6 Epigenetic regulation of ferroptosis via ETS1/miR-23a-3p/ACSL4 axis mediates sorafenib resistance in human hepatocellular carcinoma. J Exp Clin Cancer Res. 2022 Jan 3;41(1):3. doi: 10.1186/s13046-021-02208-x.
Ref 7 Sorafenib triggers ferroptosis via inhibition of HBXIP/SCD axis in hepatocellular carcinoma. Acta Pharmacol Sin. 2023 Mar;44(3):622-634. doi: 10.1038/s41401-022-00981-9. Epub 2022 Sep 15.
Ref 8 Erastin/sorafenib induces cisplatin-resistant non-small cell lung cancer cell ferroptosis through inhibition of the Nrf2/xCT pathway. Oncol Lett. 2020 Jan;19(1):323-333. doi: 10.3892/ol.2019.11066. Epub 2019 Nov 7.
Ref 9 Artesunate synergizes with sorafenib to induce ferroptosis in hepatocellular carcinoma. Acta Pharmacol Sin. 2021 Feb;42(2):301-310. doi: 10.1038/s41401-020-0478-3. Epub 2020 Jul 22.