Simeprevir induces ferroptosis through β-TrCP/Nrf2/GPX4 axis in triple-negative breast cancer cells

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Triple-negative breast cancer (TNBC) presents a significant clinical challenge due to limited effective treatments and poor patient outcomes.
• Simeprevir (SIM), an antiviral drug, has shown potential against various solid tumors, but its role in TNBC is not well understood.

Purpose of the Study:

• To investigate the anti-tumor mechanisms and therapeutic efficacy of Simeprevir (SIM) in triple-negative breast cancer (TNBC).
• To explore SIM's potential as a novel treatment strategy for TNBC.

Main Methods:

• Cell viability assays using TNBC cell lines (MDA-MB-231, BT-549).
• RNA sequencing to identify molecular pathways affected by SIM.
• Biochemical assays to measure glutathione (GSH) levels, iron levels, reactive oxygen species (ROS), and lipid peroxidation.
• Western blotting to analyze protein expression (β-TrCP, Nrf2, GPX4).
• In vivo studies using xenograft models.

Main Results:

• SIM significantly inhibited the proliferation of MDA-MB-231 and BT-549 TNBC cells.
• RNA sequencing indicated that SIM activates ferroptosis signaling in TNBC cells.
• SIM treatment led to decreased GSH levels, increased iron and ROS, and enhanced lipid peroxidation, hallmarks of ferroptosis.
• Mechanistically, SIM upregulates β-TrCP, inhibiting the Nrf2/GPX4 axis and inducing ferroptosis.
• In vivo, SIM administration suppressed tumor growth in a TNBC xenograft model by inducing ferroptosis.

Conclusions:

• Simeprevir (SIM) effectively induces ferroptosis in triple-negative breast cancer (TNBC) cells both in vitro and in vivo.
• SIM's mechanism involves the β-TrCP/Nrf2/GPX4 pathway, leading to ferroptosis.
• SIM represents a promising therapeutic candidate for TNBC treatment.