KEY TAKEAWAYS
- The study aimed to evaluate the FOXM1 inhibitor effectiveness across various HGSOC cell models to determine their activity.
- NB compounds effectively inhibit FOXM1 in HGSOC cells, meriting further exploration as potential therapeutics for HGSOC.
Genetic investigations suggest that the oncogenic transcription factor Forkhead Box M1 (FOXM1) could be a therapeutic target in high-grade serous ovarian cancer (HGSOC).
Cassie Liu and the team aimed to assess the efficacy of various FOXM1 inhibitors in cell models of HGSOC.
The study administered a series of known FOXM1 inhibitors to HGSOC and fallopian tube epithelial (FTE) cells. From the pool, compounds NB-73 and NB-115 (termed NB compounds) were selected for deeper exploration based on their potency, efficacy, and selectivity, as evaluated through cell viability assays. These NB compounds demonstrated robust and specific inhibition of FOXM1 with minimal impact on other FOX family members.
The results revealed that NB compounds reduced FOXM1 expression by targeting the FOXM1 protein, leading to its degradation via the proteasome. This suppression extended to FOXM1 gene targets at both protein and mRNA levels. NB compounds induced apoptotic cell death in HGSOC cells, which could not be reversed by a pan-caspase inhibitor, indicating specificity in FOXM1 protein loss.
Furthermore, FOXM1 reduction persisted for at least 72 hours after treatment cessation, suggesting sustained effects. These compounds effectively inhibited HGSOC cell colony formation in two-dimensional and three-dimensional settings at sub-micromolar concentrations. Additionally, NB compounds demonstrated synergistic effects with carboplatin in HGSOC cells.
The findings suggested that the NB compounds are potent, selective, and effective inhibitors of FOXM1 in HGSOC cells, warranting further exploration as potential therapeutics.
Funding was provided by the McKinsey Ovarian Cancer Research Fund, Nebraska LB506, FPBCC Pilot Project Award, FPBCC, NIH, Research Grants BRCF-083 (B.S.K.) and BRCF-084, and the Landfield Cancer Research Fund.
Source: https://pubmed.ncbi.nlm.nih.gov/38704607/
Liu C, Vorderbruggen M, Muñoz-Trujillo C, et al. (2024). “NB compounds are potent and efficacious FOXM1 inhibitors in high-grade serous ovarian cancer cells.” J Ovarian Res. 2024 May 4;17(1):94. doi: 10.1186/s13048-024-01421-4. PMID: 38704607; PMCID: PMC11069232.
