Frontiers in pharmacology · 2026
Anti-tumor activity of valproic acid in EBV-positive Burkitt lymphoma via PFN2-associated PI3K/AKT pathway repression.
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Zheng Yongliang, Yang Yuxiu, Zhang Shouhua, Liu Rui, Lin Zujie, He Yuanqiao, Luo Yaoling, He Aili
Аннотация
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.
RESULTS: 24 h IC50 values of VPA were 20.15, 4.672, 7.769 mM for Daudi, Raji, Namalwa, while 48 h IC50 decreased to 4.891, 2.283, 0.4836 mM. At 2 mM VPA treatment for 24 h, total apoptosis rates increased by 14.22% (Daudi), 10.20% (Raji), and 18.68% (Namalwa). VPA induced G0/G1 cell-cycle arrest across all 3 cell lines. In CDX and three PDX models, VPA treatment reduced tumor weight (CDX: control 1.132 g vs. VPA 0.365 g, p = 0.0207, No.1: control 1.450 g vs. VPA 1.013 g, p = 0.049, No.2: control 1.283 g vs. VPA 0.913 g, p = 0.0295, No.3: control 1.371 g vs. VPA 0.9239, p = 0.0062) without body weight loss. RNA-seq analysis identified PFN2 as an exploratory candidate transcript with nominal transcriptional downregulation upon VPA administration (log2FC = -0.3213, raw p = 0.0355, FDR = 0.6149), and KEGG enrichment revealed perturbation of the PI3K/AKT signaling pathway. VPA reduced PFN2 mRNA and protein abundance in vitro and in vivo. PFN2 knockdown recapitulated proliferation suppression and reduced p-PI3K/p-AKT levels; PFN2 overexpression partially restored cell proliferation and PI3K/AKT phosphorylation, which could be attenuated by VPA treatment. Co-administration of VPA with idelalisib or capivasertib produced stronger anti-proliferative effects of BL.
CONCLUSION: VPA exerts potent anti-tumor activity against EBV-positive BL in vitro and in multiple xenograft models, associated with PFN2 downregulation and suppressed PI3K/AKT signaling.
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.
RESULTS: 24 h IC50 values of VPA were 20.15, 4.672, 7.769 mM for Daudi, Raji, Namalwa, while 48 h IC50 decreased to 4.891, 2.283, 0.4836 mM. At 2 mM VPA treatment for 24 h, total apoptosis rates increased by 14.22% (Daudi), 10.20% (Raji), and 18.68% (Namalwa). VPA induced G0/G1 cell-cycle arrest across all 3 cell lines. In CDX and three PDX models, VPA treatment reduced tumor weight (CDX: control 1.132 g vs. VPA 0.365 g, p = 0.0207, No.1: control 1.450 g vs. VPA 1.013 g, p = 0.049, No.2: control 1.283 g vs. VPA 0.913 g, p = 0.0295, No.3: control 1.371 g vs. VPA 0.9239, p = 0.0062) without body weight loss. RNA-seq analysis identified PFN2 as an exploratory candidate transcript with nominal transcriptional downregulation upon VPA administration (log2FC = -0.3213, raw p = 0.0355, FDR = 0.6149), and KEGG enrichment revealed perturbation of the PI3K/AKT signaling pathway. VPA reduced PFN2 mRNA and protein abundance in vitro and in vivo. PFN2 knockdown recapitulated proliferation suppression and reduced p-PI3K/p-AKT levels; PFN2 overexpression partially restored cell proliferation and PI3K/AKT phosphorylation, which could be attenuated by VPA treatment. Co-administration of VPA with idelalisib or capivasertib produced stronger anti-proliferative effects of BL.
CONCLUSION: VPA exerts potent anti-tumor activity against EBV-positive BL in vitro and in multiple xenograft models, associated with PFN2 downregulation and suppressed PI3K/AKT signaling.