1. Jolkinolide B targets thioredoxin and glutathione systems to induce ROS-mediated paraptosis and apoptosis in bladder cancer cells.
- Author
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Sang J, Li W, Diao HJ, Fan RZ, Huang JL, Gan L, Zou MF, Tang GH, and Yin S
- Subjects
- Animals, Antineoplastic Combined Chemotherapy Protocols pharmacology, Cell Line, Tumor, Cell Proliferation drug effects, Cisplatin pharmacology, Drug Resistance, Neoplasm, Endoplasmic Reticulum Stress drug effects, Extracellular Signal-Regulated MAP Kinases metabolism, Humans, Male, Mice, Inbred BALB C, Mice, Nude, Thioredoxin Reductase 1 metabolism, Urinary Bladder Neoplasms enzymology, Urinary Bladder Neoplasms pathology, Xenograft Model Antitumor Assays, Mice, Antineoplastic Agents, Phytogenic pharmacology, Apoptosis drug effects, Diterpenes pharmacology, Enzyme Inhibitors pharmacology, Glutathione metabolism, Reactive Oxygen Species metabolism, Thioredoxin Reductase 1 antagonists & inhibitors, Thioredoxins metabolism, Urinary Bladder Neoplasms drug therapy
- 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., (Copyright © 2021 Elsevier B.V. All rights reserved.)
- Published
- 2021
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