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The antimetastatic effect and underlying mechanisms of thioredoxin reductase inhibitor ethaselen

Xiaoqing Zheng1, Yifan Chen1, Man Bai1

  • 1State Key Laboratory of Natural and Biomimetic Drugs, Peking University, No. 38, Xueyuan Road, Beijing 100191, PR China; Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, No. 38, Xueyuan Road, Beijing 100191, PR China.

Free Radical Biology & Medicine
|November 30, 2018
PubMed

Insights

Ethaselen (BBSKE), a thioredoxin reductase (TrxR) inhibitor, effectively suppresses cancer cell migration and invasion. This organoselenium compound shows promise in preventing and treating metastasis by targeting key molecular pathways.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Cancer metastasis significantly impacts patient survival.
  • Thioredoxin reductase (TrxR) is overexpressed in many cancers, making it a viable anti-cancer target.
  • Ethaselen (BBSKE), an organoselenium compound, is a known TrxR inhibitor with demonstrated tumor growth inhibition.

Purpose of the Study:

  • To investigate the antimetastatic effects of ethaselen (BBSKE).
  • To elucidate the underlying molecular mechanisms of BBSKE's antimetastatic action.

Main Methods:

  • In vitro studies using MCF-7 and LoVo cancer cell lines to assess migration and invasion.
  • In vivo studies using a mouse breast cancer (4T1) model.
  • Analysis of TrxR activity, reactive oxygen species (ROS), EGFR activation, HER2 expression, epithelial-to-mesenchymal transition (EMT), and expression of metastasis-associated markers (CD44, MMP-9, VEGFR2, PD-L1).
  • TrxR1-knockdown experiments in cancer cells.

Main Results:

  • BBSKE dose-dependently inhibited cancer cell migration and invasion in vitro.
  • Mechanisms involved TrxR inhibition, increased ROS, decreased EGFR activation, and reduced HER2 expression.
  • BBSKE abrogated EMT and downregulated expression of CD44, MMP-9, VEGFR2, and PD-L1.
  • In vivo, BBSKE inhibited primary tumor progression and suppressed lung and liver metastasis.
  • TrxR1 knockdown mimicked the inhibitory effects of BBSKE on migration and invasion.

Conclusions:

  • Ethaselen (BBSKE) demonstrates significant antimetastatic potential by inhibiting cancer cell migration and invasion.
  • BBSKE acts through mechanisms including TrxR inhibition and modulation of key signaling pathways and EMT.
  • BBSKE shows promise as a therapeutic agent for preventing and treating cancer metastasis.
Keywords:
Epidermal growth factor receptor (EGFR)Epithelial-mesenchymal transition (EMT)Invasion and metastasisReactive oxygen species (ROS)Thioredoxin reductase

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