Ferroptosis-centered Drug Response Information

General Information of the Drug (ID: ferrodrug0292)
Name
Apatinib
Synonyms
Apatinib; 811803-05-1; rivoceranib; Apatinib free base; N-(4-(1-Cyanocyclopentyl)phenyl)-2-((pyridin-4-ylmethyl)amino)nicotinamide; YN968D1; N-[4-(1-cyanocyclopentyl)phenyl]-2-(pyridin-4-ylmethylamino)pyridine-3-carboxamide; 5S371K6132; N-(4-(1-cyanocyclopentyl)phenyl)-2-(pyridin-4-ylmethylamino)nicotinamide; 3-Pyridinecarboxamide, N-(4-(1-cyanocyclopentyl)phenyl)-2-((4-pyridinylmethyl)amino)-; UNII-5S371K6132; apatinib (in China); RIVOCERANIB [INN]; Rivoceranib (USAN/INN); RIVOCERANIB [USAN]; RIVOCERANIB [WHO-DD]; GTPL7648; SCHEMBL1814966; CHEMBL3186534; Apatinib free base; YN-968D1; DTXSID601024366; AMY21302; BCP02840; EX-A1794; HY-13342A; MFCD21648511; NSC772886; NSC799333; s5248; AKOS024464453; CCG-268625; DB14765; DS-7455; NSC-772886; NSC-799333; SB16590; N-[4-(1-Cyanocyclopentyl)phenyl]-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide; NCGC00249393-01; NCGC00249393-08; AC-27461; BA175030; CS-0003200; C76598; D11288; AB01274807-01; AB01274807_02; Q27262801; N-[4-(1-Cyanocyclopentyl)phenyl]-2-[(4-pyridinylmethyl)amino]nicotinamide; N-[4-(1-Cyanocyclopentyl)phenyl]-2-[(pyridin-4-ylmethyl)amino]pyridine-3-carboxamide

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Structure
Formula
C24H23N5O
IUPAC Name
N-[4-(1-cyanocyclopentyl)phenyl]-2-(pyridin-4-ylmethylamino)pyridine-3-carboxamide
Canonical SMILES
C1CCC(C1)(C#N)C2=CC=C(C=C2)NC(=O)C3=C(N=CC=C3)NCC4=CC=NC=C4
InChI
InChI=1S/C24H23N5O/c25-17-24(11-1-2-12-24)19-5-7-20(8-6-19)29-23(30)21-4-3-13-27-22(21)28-16-18-9-14-26-15-10-18/h3-10,13-15H,1-2,11-12,16H2,(H,27,28)(H,29,30)
InChIKey
WPEWQEMJFLWMLV-UHFFFAOYSA-N
PubChem CID
11315474
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 Gastric cancer ICD-11: 2B72
 Disease Info 
Responsed Regulator Sterol regulatory element-binding protein 1 (SREBF1) Suppressor
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Glutathione metabolism hsa00480
Cell Process Cell ferroptosis
In Vitro Model MGC-803 cells Gastric mucinous adenocarcinoma Homo sapiens CVCL_5334
MKN45 cells Gastric adenocarcinoma Homo sapiens CVCL_0434
BGC-823 cells Gastric carcinoma Homo sapiens CVCL_3360
SGC-7901 cells Gastric carcinoma Homo sapiens CVCL_0520
AGS cells Gastric adenocarcinoma Homo sapiens CVCL_0139
In Vivo Model
Female nude mice (BALB/c, nu/nu, 18-22 g, 4-5 weeks old) were obtained from Guangdong Medical Laboratory Animal center, China, and maintained under specific pathogen-free conditions on a 12h/12h light/dark cycle. Each mouse was injected subcutaneously with eight million luciferase-expressing cells resuspended in 50 ul of PBS and 50 ul of Matrigel (BD Biosciences). When a palpable mass had developed, the mice were randomly divided into five groups: apatinib (50 mg/kg/day oral dose for 14 days); RSL3 (100 mg/kg injection of RSL3 twice per week for 2 weeks at the same site); both; apatinib (50 mg/kg/day oral dose for 14 days) plus vitamin E (100 mg/kg/day oral dose for 14 days); and vehicle (DMSO, 100 ul oral dose for 14 days).

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Response regulation Apatinib exerted antitumor effects against gastric cancer cells in vitro and in vivo through the induction of lipid peroxidation mediated by GPX4, then lead to ferroptosis. Furethermore, we found apatinib inhibited transcription of GPX4 via a SREBP1a-mediated pathway. These results indicated that GPX4 may be a potential target for anti-GC efficacy evaluation and treatment of apatinib.
Experiment 2 Reporting the Ferroptosis-centered Drug Act on This Target [4]
Target for Ferroptosis Suppressor
Responsed Disease Ovarian cancer ICD-11: 2C73
 Disease Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model A2780 cells Ovarian endometrioid adenocarcinoma Homo sapiens CVCL_0134
OVCAR-3 cells Ovarian serous adenocarcinoma Homo sapiens CVCL_0465
Response regulation Apatinib combined with olaparib-induced ferroptosis via a p53-dependent manner in ovarian cancer. Further studies showed that apatinib combined with olaparib-induced ferroptosis by inhibiting the expression of Nrf2 and autophagy, thereby inhibiting the expression of GPX4. The Nrf2 activator RTA408 and the autophagy activator rapamycin rescued the combination drug-induced ferroptosis.
Nuclear factor erythroid 2-related factor 2 (NFE2L2)
 Target Info 
In total 4 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [2]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Glioblastoma ICD-11: 2A00
 Disease Info 
Responsed Regulator Vascular endothelial growth factor receptor 2 (KDR) Driver
 Regulator Info 
Pathway Response Pathways in cancer hsa05200
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model U87 MG-Red-Fluc cells Glioblastoma Homo sapiens CVCL_5J12
U-251MG cells Astrocytoma Homo sapiens CVCL_0021
In Vivo Model
Female BALB/c nude mice (age, 4 weeks old) were purchased from Changzhou Cavens Experimental Animal Co., Ltd. (Changzhou, China).The gliomas from the nude mice were fixed in 10% paraformaldehyde at 4 for 12 h and then dehydrated in different concentrations of ethanol. The tumor tissues were permeabilized using xylene and embedded in paraffin. They were then sliced (0.5 um), rehydrated, and stained with HE at 4 for 10 min and sealed. For IHC assessment of Ki-67 in gliomas, the DAKO Envision system (Dako; Agilent Technologies, Inc.) was used.

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Response regulation Apatinib could restrain proliferation of glioma cells through induction of ferroptosis via inhibiting the activation of VEGFR2/Nrf2/Keap1 pathway. Overexpression of Nrf2 could counteract the induction of ferroptosis by apatinib.
Experiment 2 Reporting the Ferroptosis-centered Drug Act on This Target [2]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Glioblastoma ICD-11: 2A00
 Disease Info 
Responsed Regulator Kelch-like ECH-associated protein 1 (KEAP1) Driver
 Regulator Info 
Pathway Response Pathways in cancer hsa05200
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model U87 MG-Red-Fluc cells Glioblastoma Homo sapiens CVCL_5J12
U-251MG cells Astrocytoma Homo sapiens CVCL_0021
In Vivo Model
Female BALB/c nude mice (age, 4 weeks old) were purchased from Changzhou Cavens Experimental Animal Co., Ltd. (Changzhou, China).The gliomas from the nude mice were fixed in 10% paraformaldehyde at 4 for 12 h and then dehydrated in different concentrations of ethanol. The tumor tissues were permeabilized using xylene and embedded in paraffin. They were then sliced (0.5 um), rehydrated, and stained with HE at 4 for 10 min and sealed. For IHC assessment of Ki-67 in gliomas, the DAKO Envision system (Dako; Agilent Technologies, Inc.) was used.

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Response regulation Apatinib could restrain proliferation of glioma cells through induction of ferroptosis via inhibiting the activation of VEGFR2/Nrf2/ Keap1 pathway. Overexpression of Nrf2 could counteract the induction of ferroptosis by apatinib.
Experiment 3 Reporting the Ferroptosis-centered Drug Act on This Target [2]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Glioblastoma ICD-11: 2A00
 Disease Info 
Responsed Regulator Kelch-like ECH-associated protein 1 (KEAP1) Driver
 Regulator Info 
Pathway Response Pathways in cancer hsa05200
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model U87 MG-Red-Fluc cells Glioblastoma Homo sapiens CVCL_5J12
U-251MG cells Astrocytoma Homo sapiens CVCL_0021
In Vivo Model
Female BALB/c nude mice (age, 4 weeks old) were purchased from Changzhou Cavens Experimental Animal Co., Ltd. (Changzhou, China).The gliomas from the nude mice were fixed in 10% paraformaldehyde at 4 for 12 h and then dehydrated in different concentrations of ethanol. The tumor tissues were permeabilized using xylene and embedded in paraffin. They were then sliced (0.5 um), rehydrated, and stained with HE at 4 for 10 min and sealed. For IHC assessment of Ki-67 in gliomas, the DAKO Envision system (Dako; Agilent Technologies, Inc.) was used.

    Click to Show/Hide
Response regulation Apatinib could restrain proliferation of glioma cells through induction of ferroptosis via inhibiting the activation of VEGFR2/Nrf2/Keap1 pathway. Overexpression of Nrf2 could counteract the induction of ferroptosis by apatinib.
Experiment 4 Reporting the Ferroptosis-centered Drug Act on This Target [4]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Ovarian cancer ICD-11: 2C73
 Disease Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model A2780 cells Ovarian endometrioid adenocarcinoma Homo sapiens CVCL_0134
OVCAR-3 cells Ovarian serous adenocarcinoma Homo sapiens CVCL_0465
Response regulation Apatinib combined with olaparib-induced ferroptosis via a p53-dependent manner in ovarian cancer. Further studies showed that apatinib combined with olaparib-induced ferroptosis by inhibiting the expression of Nrf2 and autophagy, thereby inhibiting the expression of GPX4. The Nrf2 activator RTA408 and the autophagy activator rapamycin rescued the combination drug-induced ferroptosis.
Long-chain-fatty-acid--CoA ligase 4 (ACSL4)
 Target Info 
In total 1 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [3]
Target for Ferroptosis Driver
Responsed Disease Colorectal cancer ICD-11: 2B91
 Disease Info 
Responsed Regulator Elongation of very long chain fatty acids protein 6 (ELOVL6) Suppressor
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model HCT 116 cells Colon carcinoma Homo sapiens CVCL_0291
HIEC-6 cells Normal Homo sapiens CVCL_6C21
Response regulation ACSL4, a vital regulator of ferroptosis, could interact with ELOVL6 directly. Apatinib promoted ferroptosis in colorectal cancer (CRC) cells by targeting ELOVL6/ACSL4, providing a new mechanism support for apatinib application in the clinical treatment of CRC.
Unspecific Target
In total 1 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [4]
Responsed Disease Ovarian cancer ICD-11: 2C73
 Disease Info 
Responsed Regulator Cellular tumor antigen p53 (TP53) Driver
 Regulator Info 
Pathway Response Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model A2780 cells Ovarian endometrioid adenocarcinoma Homo sapiens CVCL_0134
OVCAR-3 cells Ovarian serous adenocarcinoma Homo sapiens CVCL_0465
Response regulation Apatinib combined with olaparib-induced ferroptosis via a p53-dependent manner in ovarian cancer. Further studies showed that apatinib combined with olaparib-induced ferroptosis by inhibiting the expression of Nrf2 and autophagy, thereby inhibiting the expression of GPX4. The Nrf2 activator RTA408 and the autophagy activator rapamycin rescued the combination drug-induced ferroptosis.
References
Ref 1 Apatinib induced ferroptosis by lipid peroxidation in gastric cancer. Gastric Cancer. 2021 May;24(3):642-654. doi: 10.1007/s10120-021-01159-8. Epub 2021 Feb 5.
Ref 2 Apatinib Induces Ferroptosis of Glioma Cells through Modulation of the VEGFR2/Nrf2 Pathway. Oxid Med Cell Longev. 2022 May 11;2022:9925919. doi: 10.1155/2022/9925919. eCollection 2022.
Ref 3 Apatinib Promotes Ferroptosis in Colorectal Cancer Cells by Targeting ELOVL6/ACSL4 Signaling. Cancer Manag Res. 2021 Feb 11;13:1333-1342. doi: 10.2147/CMAR.S274631. eCollection 2021.
Ref 4 Apatinib combined with olaparib induces ferroptosis via a p53-dependent manner in ovarian cancer. J Cancer Res Clin Oncol. 2023 Sep;149(11):8681-8689. doi: 10.1007/s00432-023-04811-1. Epub 2023 Apr 29.