Frontiers in pharmacology
Anti-tumor activity of valproic acid in EBV-positive Burkitt lymphoma via PFN2-associated PI3K/AKT pathway repression
Door Zheng Y, Yang Y, Zhang S en 5 anderen.
Inhoud in het Engels
Abstract
Background
Burkitt lymphoma (BL) has limited therapies and poor prognosis in elderly or relapsed patients. Valproic acid (VPA) exhibits broad anti-tumor activity, but its quantitative efficacy and molecular mechanism in EBV-positive BL remain undefined.
Methods
VPA activity in Daudi, Raji, Namalwa BL cell lines (n = 3 biological replicates per assay) was assessed using CCK-8 viability (24 h/48 h IC50 values), EdU proliferation, PI cell-cycle, and Annexin V/PI dual-staining apoptosis assays. In vivo efficacy was tested in Namalwa CDX (control n = 5, VPA n = 6) and three independent EBV-positive PDX models (6 mice/group for each PDX line), with daily 400 mg/kg intraperitoneal VPA administration for 1-3 weeks; ex vivo drug response of PDX fragments was quantified via hydrogel embedded histoculture drug sensitivity test (HDST). RNA-seq was conducted on PDX No.1 tumor tissues (VPA vs. saline control, n = 3 per group). PFN2 and PI3K/AKT pathway alterations were validated by RT-qPCR, Western blot, PFN2 knockdown/overexpression, and PI3K/AKT inhibitor combination assays.