Ferroptosis-centered Drug Response Information

General Information of the Drug (ID: ferrodrug0335)
Name
RSL3
Synonyms
RSL3; 1219810-16-8; 1S,3R-RSL3; RSL3 1S,3R-; (1S,3R)-RSL3; RSL3 (1S,3R-); CHEMBL4747331; (1S,3R)-Methyl 2-(2-chloroacetyl)-1-(4-(methoxycarbonyl)phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate; methyl (1S,3R)-2-(2-chloroacetyl)-1-(4-(methoxycarbonyl)phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate; methyl (1S,3R)-2-(2-chloroacetyl)-1-[4-(methoxycarbonyl)phenyl]-1H,2H,3H,4H,9H-pyrido[3,4-b]indole-3-carboxylate; methyl (1S,3R)-2-(2-chloroacetyl)-1-(4-methoxycarbonylphenyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole-3-carboxylate; RSL3 1S; SCHEMBL13402744; EX-A1392; BDBM50547192; NSC833292; s8155; AKOS030632788; CCG-269132; CS-5650; HY-100218A; NSC-833292; CID 1750826; AC-35345; AS-55795; K601; C21479; C71823; EN300-7365470; Q55879537; (1S,3R)-Methyl 2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1-[4-(methoxycarbonyl)phenyl]-1H-pyrido[3,4-b]indole-3-carboxylate

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Status
Investigative
Drug Type
Small molecular drug
Structure
Formula
C23H21ClN2O5
IUPAC Name
methyl (1S,3R)-2-(2-chloroacetyl)-1-(4-methoxycarbonylphenyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole-3-carboxylate
Canonical SMILES
COC(=O)C1CC2=C(C(N1C(=O)CCl)C3=CC=C(C=C3)C(=O)OC)NC4=CC=CC=C24
InChI
InChI=1S/C23H21ClN2O5/c1-30-22(28)14-9-7-13(8-10-14)21-20-16(15-5-3-4-6-17(15)25-20)11-18(23(29)31-2)26(21)19(27)12-24/h3-10,18,21,25H,11-12H2,1-2H3/t18-,21+/m1/s1
InChIKey
TXJZRSRTYPUYRW-NQIIRXRSSA-N
PubChem CID
1750826
Full List of Ferroptosis Target Related to This Drug
Phospholipid hydroperoxide glutathione peroxidase (GPX4)
 Target Info 
In total 3 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [1]
Target for Ferroptosis Suppressor
Responsed Disease Pancreatic cancer ICD-11: 2C10
 Disease Info 
Responsed Regulator Nonsense-mediated mRNA decay factor SMG9 (SMG9) Driver
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model PANC-1 cells Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0480
HT-1080 cells Fibrosarcoma Homo sapiens CVCL_0317
In Vivo Model
To generate murine subcutaneous tumors, 5 x 106 PANC1 cells in 100 ul PBS were injected subcutaneously to the right of the dorsal midline in 6- to 8-week-oldathymic nude mice(n = 5 mice/group). After the tumor reached 60-80 mm3 on day 7, the mice were randomly grouped and then given intratumoral treatment with RSL3 (50 mg/kg, once every other day) at day 7 for 2 weeks.

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Response regulation SMG9, a component of the NMD machinery, is a selective driver for ferroptosis in pancreatic cancer cells. SMG9 is a direct binding protein of GPX4 to promote the degradation of GPX4 in response to RSL3 (a GPX4 inhibitor), but not erastin (a SLC7A11 inhibitor).
Experiment 2 Reporting the Ferroptosis-centered Drug Act on This Target [3]
Target for Ferroptosis Suppressor
Responsed Disease Glioblastoma ICD-11: 2A00
 Disease Info 
Pathway Response NF-kappa B signaling pathway hsa04064
Fatty acid metabolism hsa01212
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 B-NDG mice (4-6 weeks old, 16-20 g) were purchased from Biocytogen (Biocytogen Jiangsu Co., Ltd., Jiangsu, China) and housed under specific pathogen-free conditions. 5 x 106 U87 cells were resuspended in 200 uL PBS buffer and then inoculated into the left hind limb of each mouse. Once tumor volumes reached >=50 mm3, the mice were randomly divided into four groups (n = 5): the control, RSL3-only, BAY-only, and RSL3 plus BAY groups. Chemicals were administered through intratumor injection (100 mg/kg for RSL3 and 1 mg/kg for BAY 11-7082) biweekly for two weeks.

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Response regulation NF-kB pathway activation is vital for RSL3-induced ferroptosis in glioblastoma cells both in vitro and in vivo. Furthermore, RNAi-mediated GPX4 silencing cannot trigger ferroptosis in glioblastoma cells unless the NF-kB pathway is activated simultaneously. Finally, NF-kB pathway activation promotes ferroptosis by downregulating the expression of ATF4 and SLC7A11.
Experiment 3 Reporting the Ferroptosis-centered Drug Act on This Target [5]
Target for Ferroptosis Suppressor
Responsed Disease Colorectal cancer ICD-11: 2B91
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
In Vitro Model HCT 116 cells Colon carcinoma Homo sapiens CVCL_0291
HT29 cells Colon cancer Mus musculus CVCL_A8EZ
LoVo cells Colon adenocarcinoma Homo sapiens CVCL_0399
Response regulation RSL3 triggered ferroptotic cell death by promoting the accumulation of cellular ROS and increasing the cellular LIP level. Mechanismly, we found transferrin expression were elevated in colorectal cancer cells treated with RSL3 accompanied by a decrease in the expression of GPX4, indicating an iron-dependent cell death.
Nuclear factor erythroid 2-related factor 2 (NFE2L2)
 Target Info 
In total 1 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [2]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Lung cancer ICD-11: 2C25
 Disease Info 
Responsed Regulator Ubiquitin carboxyl-terminal hydrolase 11 (USP11) Suppressor
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Ubiquitin mediated proteolysis hsa04120
Cell Process Cell ferroptosis
In Vitro Model A-549 cells Lung adenocarcinoma Homo sapiens CVCL_0023
H2122 cells Lung adenocarcinoma Homo sapiens CVCL_1531
In Vivo Model
After two weeks in house, the mice were subcutaneously injected with A549 cells (100 uL containing 5 x 106 cells/injection) and monitored for tumor cell xenografts to reach approximately 100 mm3. The mice were then divided into two groups (n = 5), the RSL3 treatment (100 mg/kg; dissolved in 5% dimethyl sulfoxide/corn oil; administrated intratumorally twice a day for one week) and control (5% dimethyl sulfoxide/corn oil only) groups.

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Response regulation RSL3 was able to directly bind to USP11, a recently identified de-ubiquitinase of NRF2, and inactivate USP11 protein to induce NRF2 protein ubiquitination and degradation in KLK lung adenocarcinoma cells.
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 [3]
Target for Ferroptosis Suppressor
Responsed Disease Glioblastoma ICD-11: 2A00
 Disease Info 
Responsed Regulator NF-kappa-B inhibitor alpha (NFKBIA) Driver
 Regulator Info 
Pathway Response NF-kappa B signaling pathway hsa04064
Fatty acid metabolism hsa01212
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 B-NDG mice (4-6 weeks old, 16-20 g) were purchased from Biocytogen (Biocytogen Jiangsu Co., Ltd., Jiangsu, China) and housed under specific pathogen-free conditions. 5 x 106 U87 cells were resuspended in 200 uL PBS buffer and then inoculated into the left hind limb of each mouse. Once tumor volumes reached >=50 mm3, the mice were randomly divided into four groups (n = 5): the control, RSL3-only, BAY-only, and RSL3 plus BAY groups. Chemicals were administered through intratumor injection (100 mg/kg for RSL3 and 1 mg/kg for BAY 11-7082) biweekly for two weeks.

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Response regulation NF-kB pathway activation is vital for RSL3-induced ferroptosis in glioblastoma cells both in vitro and in vivo. Furthermore, RNAi-mediated GPX4 silencing cannot trigger ferroptosis in glioblastoma cells unless the NF-kB pathway is activated simultaneously. Finally, NF-kB pathway activation promotes ferroptosis by downregulating the expression of ATF4 and SLC7A11.
Unspecific Target
In total 2 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [3]
Responsed Disease Glioblastoma ICD-11: 2A00
 Disease Info 
Responsed Regulator Cyclic AMP-dependent transcription factor ATF-4 (ATF4) Suppressor
 Regulator Info 
Pathway Response NF-kappa B signaling pathway hsa04064
Fatty acid metabolism hsa01212
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 B-NDG mice (4-6 weeks old, 16-20 g) were purchased from Biocytogen (Biocytogen Jiangsu Co., Ltd., Jiangsu, China) and housed under specific pathogen-free conditions. 5 x 106 U87 cells were resuspended in 200 uL PBS buffer and then inoculated into the left hind limb of each mouse. Once tumor volumes reached >=50 mm3, the mice were randomly divided into four groups (n = 5): the control, RSL3-only, BAY-only, and RSL3 plus BAY groups. Chemicals were administered through intratumor injection (100 mg/kg for RSL3 and 1 mg/kg for BAY 11-7082) biweekly for two weeks.

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Response regulation NF-kB pathway activation is vital for RSL3-induced ferroptosis in glioblastoma cells both in vitro and in vivo. Furthermore, RNAi-mediated GPX4 silencing cannot trigger ferroptosis in glioblastoma cells unless the NF-kB pathway is activated simultaneously. Finally, NF-kB pathway activation promotes ferroptosis by downregulating the expression of ATF4 and SLC7A11.
Experiment 2 Reporting the Ferroptosis-centered Drug Act on This Target [4]
Responsed Disease Hepatocellular carcinoma ICD-11: 2C12
 Disease Info 
Responsed Regulator Ceruloplasmin (CP) 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
Hep 3B2.1-7 cells Hepatocellular carcinoma Homo sapiens CVCL_0326
HEK-293T cells Normal Homo sapiens CVCL_0063
Response regulation Erastin and RSL3 suppress ceruloplasmin expression in hepatocellular carcinoma cells. CP suppresses ferroptosis by regulating iron homeostasis in hepatocellular carcinoma cells. The suppression function of ceruloplasmin in erastin- and RSL3-induced ferroptosis is dependent on FPN.
References
Ref 1 SMG9 drives ferroptosis by directly inhibiting GPX4 degradation. Biochem Biophys Res Commun. 2021 Aug 27;567:92-98. doi: 10.1016/j.bbrc.2021.06.038. Epub 2021 Jun 16.
Ref 2 The RSL3 Induction of KLK Lung Adenocarcinoma Cell Ferroptosis by Inhibition of USP11 Activity and the NRF2-GSH Axis. Cancers (Basel). 2022 Oct 25;14(21):5233. doi: 10.3390/cancers14215233.
Ref 3 RSL3 Drives Ferroptosis through NF-B Pathway Activation and GPX4 Depletion in Glioblastoma. Oxid Med Cell Longev. 2021 Dec 26;2021:2915019. doi: 10.1155/2021/2915019. eCollection 2021.
Ref 4 Ceruloplasmin suppresses ferroptosis by regulating iron homeostasis in hepatocellular carcinoma cells. Cell Signal. 2020 Aug;72:109633. doi: 10.1016/j.cellsig.2020.109633. Epub 2020 Apr 10.
Ref 5 RSL3 Drives Ferroptosis Through GPX4 Inactivation and ROS Production in Colorectal Cancer. Front Pharmacol. 2018 Nov 22;9:1371. doi: 10.3389/fphar.2018.01371. eCollection 2018.