Herceptin induces ferroptosis and mitochondrial dysfunction in H9c2 cells

Area of Science:

• Cardiology
• Oncology
• Cell Biology
• Pharmacology

Background:

• Ferroptosis, a regulated form of cell death, is implicated in cardiomyopathy development.
• Herceptin (trastuzumab) is a HER2-targeting therapy for HER2-positive breast cancer, but its use is limited by cardiotoxicity.
• Understanding the mechanisms of Herceptin-induced cardiotoxicity is crucial for patient safety.

Purpose of the Study:

• To investigate if targeting ferroptosis can prevent Herceptin-induced heart failure.
• To explore the role of ferroptosis in an in vitro model of Herceptin cardiotoxicity using H9c2 cells.

Main Methods:

• H9c2 cells were treated with Herceptin, Herceptin + ferrostatin-1 (Fer-1), or Herceptin + deferoxamine.
• Cell viability (MTT assay), reactive oxygen species (ROS) levels (DCFH-DA, MitoSOX Red), glutathione (GSH)/oxidized glutathione (GSSG) ratio, mitochondrial membrane potential (JC-1), and ATP content were assessed.
• Protein expressions of key ferroptosis and mitochondrial dynamics markers were evaluated by Western blotting.

Main Results:

• Herceptin reduced H9c2 cell viability and increased ROS and iron levels, while decreasing GSH/GSSG ratio and mitochondrial function.
• Ferrostatin-1 treatment reversed Herceptin-induced cell death, oxidative stress, and mitochondrial dysfunction.
• Ferrostatin-1 partially restored protein expression of ferroptosis regulators (GPX4, SLC7A11) and mitochondrial proteins, though deferoxamine showed stronger effects.

Conclusions:

• Herceptin-induced cardiotoxicity in H9c2 cells is mediated by ferroptosis.
• Targeting ferroptosis with inhibitors like ferrostatin-1 shows potential for preventing Herceptin-induced heart failure.
• These findings offer insights into Herceptin cardiotoxicity mechanisms and suggest novel therapeutic strategies for HER2+ breast cancer patients.