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

Jun Sang1, Wei Li1, Hong-Juan Diao1

  • 1School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510006, China.

Cancer Letters
|April 9, 2021
PubMed

Insights

Jolkinolide B (JB) effectively combats bladder cancer by inducing cell death through multiple pathways. This compound shows promise for developing new treatments against drug-resistant bladder tumors.

Area of Science:

  • Oncology
  • Pharmacology
  • Biochemistry

Background:

  • Bladder cancer presents significant clinical heterogeneity and a poor prognosis.
  • Existing treatments face challenges with cisplatin-resistant tumors.
  • Novel therapeutic agents are urgently needed for bladder cancer treatment.

Purpose of the Study:

  • To identify and characterize novel anti-bladder cancer agents from a Euphorbiaceae diterpenoid library.
  • To investigate the mechanisms of action of the identified agent, Jolkinolide B (JB).
  • To evaluate the therapeutic potential of JB against both sensitive and resistant bladder cancer models.

Main Methods:

  • Anti-proliferation assays were used to screen the diterpenoid library.
  • Cytotoxicity was assessed against various bladder cancer cell lines.
  • In vivo efficacy was evaluated using cisplatin-resistant bladder cancer xenografts.
  • Mechanistic studies involved analyzing apoptosis, paraptosis, reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), thioredoxin reductase 1 (TrxR1), and glutathione (GSH) levels.

Main Results:

  • Jolkinolide B (JB) demonstrated significant cytotoxicity against bladder cancer cell lines.
  • JB suppressed the growth of cisplatin-resistant bladder cancer xenografts in monotherapy and combination treatments.
  • JB induced apoptosis via MAPK pathways and paraptosis through ROS-mediated ER stress and ERK activation.
  • JB's mechanism involves inhibiting TrxR1 and depleting GSH, leading to excessive ROS production.

Conclusions:

  • Jolkinolide B (JB) is a potent anti-bladder cancer agent with a dual mechanism of cell death induction.
  • JB targets the thioredoxin and glutathione systems, highlighting its unique mode of action.
  • JB shows significant therapeutic potential for developing novel drugs against bladder cancer, including resistant forms.
Keywords:
Cytoplasmic vacuolizationDrug resistanceEndoplasmic reticulum stressMitogen-activated protein kinasesNatural product

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