Valproic Acid Sensitizes Glioma Cells to Luteolin Through Induction of Apoptosis and Autophagy via Akt Signaling

Glioma is a highly malignant type of intracranial tumor with a poor prognosis resulting from traditional chemo-resistance with temozolomide (TMZ). Luteolin has been detected to exert limited anti-tumor effects on gliomas, while valproic acid (VPA) is a common chemotherapy sensitizer in the treatment of tumors. In this study, three glioma cell lines including U251, LN229 and SNB19 were selected for evaluation of combined anti-tumor effects of VPA and luteolin via Cell Counting Kit-8 (CCK-8) assay, colony formation assay, wound-healing assay, flow cytometry and western blot assay. The results disclosed that VPA sensitized glioma cells to luteolin by repressing cell viability, colony formation and migration. Mechanically, VPA boosted cellular apoptosis and cell-cycle arrest by increased level of cleaved caspase-3/caspase-3, cleaved PARP/PARP and Bax/Bcl-2. In addition, VPA also facilitated cellular autophagy via the decline of p62, p-Akt/Akt and the accumulation of LC3-II. These findings suggested that VPA enhanced the anticancer effects of luteolin by strengthening apoptosis and autophagy via Akt signaling, which could be adopted as a novel therapy for glioma.