Ferroptosis-centered Drug Response Information

General Information of the Drug (ID: ferrodrug0243)
Name
Pseudolaric acid B
Synonyms
Pseudolaric acid B; 82508-31-4; Pseudolaric-Acid-B; Pseudolaric acid b(pba); CHEBI:189471; BCP07962; PD087135; Q-100841; (2E,4E)-5-[(1S,7S,8S,9R)-7-Acetyloxy-4-methoxycarbonyl-9-methyl-11-oxo-10-oxatricyclo[6.3.2.01,7]tridec-3-en-9-yl]-2-methylpenta-2,4-dienoic acid

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Structure
3D MOL
2D MOL
Formula
C23H28O8
IUPAC Name
(2E,4E)-5-[(1S,7S,8S,9R)-7-acetyloxy-4-methoxycarbonyl-9-methyl-11-oxo-10-oxatricyclo[6.3.2.01,7]tridec-3-en-9-yl]-2-methylpenta-2,4-dienoic acid
Canonical SMILES
CC(=CC=CC1(C2CCC3(C2(CCC(=CC3)C(=O)OC)OC(=O)C)C(=O)O1)C)C(=O)O
InChI
InChI=1S/C23H28O8/c1-14(18(25)26)6-5-10-21(3)17-9-12-22(20(28)31-21)11-7-16(19(27)29-4)8-13-23(17,22)30-15(2)24/h5-7,10,17H,8-9,11-13H2,1-4H3,(H,25,26)/b10-5+,14-6+/t17-,21+,22-,23-/m0/s1
InChIKey
VDGOFNMYZYBUDT-YCONPBHISA-N
PubChem CID
71307573
Full List of Ferroptosis Target Related to This Drug
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 [1]
Target for Ferroptosis Suppressor
Responsed Disease Glioblastoma ICD-11: 2A00
 Disease Info 
Responsed Regulator Cellular tumor antigen p53 (TP53) Driver
 Regulator Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model U-87MG cells Glioblastoma Homo sapiens CVCL_0022
U-251MG cells Astrocytoma Homo sapiens CVCL_0021
SHG-44 cells Astrocytoma Homo sapiens CVCL_6728
In Vivo Model
Twenty athymic BALB/c nude mice (aged 4 weeks, weight 20-22 g, from Shanghai laboratory animal Center, Shanghai, China) were housed in a specific pathogen-free environment. A total of 1 x 106 logarithmically growing C6 cells in 100 uL of PBS were subcutaneously injected into the right flank of each mouse. Therapeutic experiments were started when the tumor reached about 150 mm3 after about 7 days. The mice were allocated to receive intraperitoneal injections of vehicle (control group, n = 5/group), PAB at the dosage of 10 mg/kg body weight (n = 10/group) and 20 mg/kg body weight (n = 10/group) in the same volume 50 uL once a days for 8 times.

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Response regulation Pseudolaric acid B (PAB) improved intracellular iron by upregulation of transferrin receptor. The increased iron activated Nox4, which resulted in overproduction of H2O2and lipid peroxides. Moreover, PAB depleted intracellular GSH via p53-mediated xCT (SLC7A11) pathway, which further exacerbated accumulation of H2O2and lipid peroxides. Thus, PAB triggers ferroptosis in glioma cells and is a potential medicine for glioma treatment.
NADPH oxidase 4 (NOX4)
 Target Info 
In total 1 item(s) under this Target
Experiment 1 Reporting the Ferroptosis-centered Drug Act on This Target [1]
Target for Ferroptosis Driver
Responsed Disease Glioblastoma ICD-11: 2A00
 Disease Info 
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
Cell proliferation
In Vitro Model U-87MG cells Glioblastoma Homo sapiens CVCL_0022
U-251MG cells Astrocytoma Homo sapiens CVCL_0021
SHG-44 cells Astrocytoma Homo sapiens CVCL_6728
In Vivo Model
Twenty athymic BALB/c nude mice (aged 4 weeks, weight 20-22 g, from Shanghai laboratory animal Center, Shanghai, China) were housed in a specific pathogen-free environment. A total of 1 x 106 logarithmically growing C6 cells in 100 uL of PBS were subcutaneously injected into the right flank of each mouse. Therapeutic experiments were started when the tumor reached about 150 mm3 after about 7 days. The mice were allocated to receive intraperitoneal injections of vehicle (control group, n = 5/group), PAB at the dosage of 10 mg/kg body weight (n = 10/group) and 20 mg/kg body weight (n = 10/group) in the same volume 50 uL once a days for 8 times.

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Response regulation Pseudolaric acid B (PAB) improved intracellular iron by upregulation of transferrin receptor. The increased iron activated Nox4, which resulted in overproduction of H2O2and lipid peroxides. Moreover, PAB depleted intracellular GSH via p53-mediated xCT pathway, which further exacerbated accumulation of H2O2and lipid peroxides. Thus, PAB triggers ferroptosis in glioma cells and is a potential medicine for glioma treatment.
References
Ref 1 Pseudolaric acid B triggers ferroptosis in glioma cells via activation of Nox4 and inhibition of xCT. Cancer Lett. 2018 Aug 1;428:21-33. doi: 10.1016/j.canlet.2018.04.021. Epub 2018 Apr 24.