Levistilide a Induces Ferroptosis by Activating the Nrf2/HO-1 Signaling Pathway in Breast Cancer Cells

Drug Des Devel Ther. 2022 Sep 7:16:2981-2993. doi: 10.2147/DDDT.S374328. eCollection 2022.

Abstract

Introduction: Breast cancer (BC) is the leading female malignancy, with one million new cases diagnosed worldwide per year. However, the current treatment options for BC patients have difficulty achieving satisfactory efficacy. Ferroptosis is a new mode of regulated cell death that plays a key role in the inhibition of tumorigenesis. Levistilide A (LA), as an active compound extracted from Chuanxiong Rhizoma, might prevent the development of tumors by regulating the critical cellular processes of ferroptosis.

Methods: In this study, the underlying mechanisms of LA on ferroptosis in BC were explored in vitro. The effect of LA on the viability and mitochondrial function of BC cells was determined. Moreover, the effect of LA on the expression levels of key molecules involved in ferroptosis and the nuclear factor erythroid-2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) signaling pathway was evaluated.

Results: LA significantly reduced cell viability and damaged the mitochondrial structure and function of BC cells in a dose-dependent manner. Furthermore, LA treatment markedly enhanced reactive oxygen species (ROS)-induced ferroptosis by activating the Nrf2/HO-1 signaling pathway.

Conclusion: These findings suggest that LA may be a potential lead compound for breast cancer therapy by inducing ferroptosis in tumor cells.

Keywords: Nrf2/HO-1 signaling pathway; breast cancer; ferroptosis; levistilide A.

MeSH terms

  • Breast Neoplasms* / drug therapy
  • Female
  • Ferroptosis*
  • Heme Oxygenase-1 / metabolism
  • Heterocyclic Compounds, Bridged-Ring
  • Humans
  • NF-E2-Related Factor 2 / metabolism
  • Signal Transduction

Substances

  • Heterocyclic Compounds, Bridged-Ring
  • NF-E2-Related Factor 2
  • levistilide A
  • HMOX1 protein, human
  • Heme Oxygenase-1

Grants and funding

This work was supported by the National Natural Science Foundation of China (No. 81774261), Guangdong Province Science and Technology Plan International Cooperation Project (No. 2020A0505100052), Natural Science Foundation of Guangdong Province (No. 2022A1515011260), Guangzhou Science and Technology Plan Project (No. 202002020033), and Guangzhou Science and Technology Plan Project (202102010178).