Jolkinolide B targets thioredoxin and glutathione systems to induce ROS-mediated paraptosis and apoptosis in bladder cancer cells

  • Cancer Lett. 2021 Jul 1;509:13-25. doi: 10.1016/j.canlet.2021.03.030.
Jun Sang  1 ,  Wei Li  1 ,  Hong-Juan Diao  1 ,  Run-Zhu Fan  1 ,  Jia-Luo Huang  1 ,  Lu Gan  1 ,  Ming-Feng Zou  1 ,  Gui-Hua Tang  1 ,  Sheng Yin  2
Affiliations
  • 1. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China.
  • 2. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China. Electronic address: [email protected].
PMID: 33836250 DOI: 10.1016/j.canlet.2021.03.030
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.

Keywords
Cytoplasmic vacuolization; Drug resistance; Endoplasmic reticulum stress; Mitogen-activated protein kinases; Natural product.
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