The natural compound n-butylidenephthalide suppresses type II ovarian cancer cell growth by inducing ferroptosis.

Abstract

Type II high-grade serous ovarian cancer (HGSOC) accounts for 80% of all ovarian cancers. Tumor metastasis and chemotherapy resistance are predominantly caused by cancer stem cells (CSCs). n-butylidenephthalide (BP) has showed promise as an anti-tumor drug in a variety of malignancies. The purpose of this study was to examine the ferroptosis influence of BP on HGSOC. CSCs were isolated from the HGSOC cell lines KURAMOCHI and OVSAHO by employing the CSC marker ALDH. The study assessed cell survival, proliferation, IC₅₀ (the concentration at which 50% growth suppression occurs), terminal deoxynucleotidyl transferase (TdT) dUTP nick end labeling (TUNEL) assay, and Western blot analysis of ovarian cancer cells and CSCs. qPCR was performed to assess ferroptosis-related gene expression. Furthermore, animal studies were carried out using a mouse model with subcutaneous xenografted stemness-enriched ovarian CSCs and evaluated with an IVIS scan. In this in vivo investigation, control, BP with or without taxol or ferrostatin were intended as cancer treatments. The findings indicated that BP inhibits HGSOC growth via ferroptosis mediated by the GPX4 conventional and HMBOX-1 noncanonical pathways. Furthermore, the anti-tumor effects of BP and Taxol were significantly improved when tumor-bearing mice were treated with both simultaneously, compared to their sole therapy. BP may increase the susceptibility of ovarian cancer cells to Taxol, implying its potential to improve the therapeutic effects of this standard ovarian cancer treatment.