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Amitriptyline inhibits EAG1 channels by binding to their PAS domains and exerts EAG1-dependent anti-tumorigenic

Joos Berghausen1, Clementine A D Thomas1, Ze-Jun Wang1

  • 1Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC, USA.

Cancer Gene Therapy
|April 16, 2026
PubMed

Insights

Amitriptyline (AmiT) inhibits Ether-a-go-go 1 (EAG1) potassium channels, demonstrating EAG1-dependent anti-tumorigenic effects. This suggests repurposing AmiT as a potential cancer treatment for tumors with high EAG1 expression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Ether-a-go-go 1 (EAG1) potassium channels are frequently overexpressed in various cancers.
  • EAG1 channel activity is linked to increased cancer cell growth and migration.
  • Existing treatments for cancer often have limitations, necessitating novel therapeutic strategies.

Purpose of the Study:

  • To investigate the anti-cancer potential of amitriptyline (AmiT).
  • To determine if AmiT exerts its effects by targeting EAG1 potassium channels.
  • To explore the EAG1-dependent anti-tumorigenic effects of AmiT.

Main Methods:

  • Cell culture experiments using cancer cell lines (MDA-MB-231, SH-SY5Y, A375) and HEK293 cells with modified EAG1 expression (knock-in/knock-out).
  • Assessment of cell growth inhibition and cell migration using in vitro assays.
  • Zebrafish xenograft models to evaluate AmiT's efficacy in vivo.

Main Results:

  • Amitriptyline (AmiT) inhibited the growth and migration of cancer cells with high EAG1 expression.
  • EAG1 expression levels correlated with AmiT's inhibitory effects on cell growth and migration.
  • AmiT demonstrated efficacy in reducing tumor growth in zebrafish xenografts expressing high levels of EAG1.

Conclusions:

  • EAG1 potassium channels are a functional molecular target of amitriptyline (AmiT).
  • AmiT exhibits significant EAG1-dependent anti-tumorigenic effects.
  • Amitriptyline shows promise for repurposing as an anti-cancer agent, particularly for tumors with elevated EAG1 expression.

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