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Jolkinolide B targets thioredoxin and glutathione systems to induce ROS-mediated paraptosis and apoptosis in bladder cancer cells
- Source :
- Cancer letters. 509
- Publication Year :
- 2021
-
Abstract
- Bladder cancer is a clinically heterogeneous disease with a poor prognosis. In the current study, anti-proliferation assay of a Euphorbiaceae diterpenoid library led to the identification of an anti-bladder cancer agent Jolkinolide B (JB). JB showed significant cytotoxicity against a panel of bladder cancer cell lines and suppressed the growth of cisplatin (CDDP)-resistant bladder cancer xenografts in single or combination treatments. Mechanistic study revealed that, besides inducing mitogen-activated protein kinase (MAPK)-related apoptosis, JB could trigger the paraptosis via activation of reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress and extracellular signal-regulated kinase (ERK) pathway. The excessive production of ROS could be induced by JB via inhibition of thioredoxin reductase 1 (TrxR1) and depletion of glutathione (GSH). Collectively, JB that targets thioredoxin and GSH systems to induce two distinct cell death modes may serve as a promising candidate in future anti-bladder cancer drug development.
- Subjects :
- 0301 basic medicine
MAPK/ERK pathway
Male
Cancer Research
Programmed cell death
Thioredoxin Reductase 1
Mice, Nude
Apoptosis
Paraptosis
03 medical and health sciences
0302 clinical medicine
Thioredoxins
Cell Line, Tumor
Antineoplastic Combined Chemotherapy Protocols
medicine
Animals
Humans
Enzyme Inhibitors
Extracellular Signal-Regulated MAP Kinases
Cell Proliferation
Cisplatin
Mice, Inbred BALB C
Chemistry
Cancer
medicine.disease
Endoplasmic Reticulum Stress
Antineoplastic Agents, Phytogenic
Glutathione
Xenograft Model Antitumor Assays
030104 developmental biology
Oncology
Urinary Bladder Neoplasms
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
Cancer research
Thioredoxin
Diterpenes
Reactive Oxygen Species
medicine.drug
Subjects
Details
- ISSN :
- 18727980
- Volume :
- 509
- Database :
- OpenAIRE
- Journal :
- Cancer letters
- Accession number :
- edsair.doi.dedup.....f26775b925964bd1db065384f1ca4e3a