Pulrodemstat, a selective inhibitor of KDM1A, suppresses head and neck squamous cell carcinoma growth by triggering apoptosis

作者：Cheng Jiang, Xiaofeng Weng, Yuqing Chen, Junjun Yang · 发表于：BMC Pharmacology and Toxicology · 年份：2024 · DOI：10.1186/s40360-024-00807-w · 被引用次数：3 · 研究领域：Epigenetics and DNA Methylation、Ferroptosis and cancer prognosis、Histone Deacetylase Inhibitors Research

BACKGROUND: Chemotherapy is often ineffective as a first-line treatment for head and neck squamous cell carcinoma (HNSCC), and a more precise and effective therapeutic option is urgently needed. METHODS: High-throughput screening of a histone demethylase inhibitor library was performed to identify potential drugs for treating HNSCC. The Cancer Genome Atlas (TCGA) and single-cell sequencing were used to evaluate the potential diagnostic value and expression distribution of candidate drug targets. Colony formation, transwell assays, and flow cytometry analyses were used to assess the antitumor function of the potential drugs. The CCK-8 assay was used to compare the antitumor activity of the candidate drug and the traditional chemotherapy drug. Bioinformatic analysis based on TCGA database was used for unveiling the upstream signaling. RESULTS: analysis revealed that Pulrodemstat might possess stronger anti-tumor activity than 5-Fu. Additionally, Pulrodemstat dramatically suppressed HNSCC cell proliferation and migration without inducing toxicity in normal cells. TCGA analysis revealed that KDM1A is positively associated with tumor proliferation, DNA repair, and DNA replication in HNSCC. Consistent with these results, Pulrodemstat substantially induced apoptosis in the HNSCC cells. Furthermore, TCGA analysis revealed that KDM1A was aberrantly overexpressed in HNSCC, positively correlated with malignancy, and negatively associated with the clinical outcomes of HNSCC patients. Not...