Valproic acid sensitizes resveratrol to induce glioma cell apoptosis via the ROS-PDCD4-Bax signaling axis.

BACKGROUND: Glioma is an aggressive malignant brain tumor with poor prognosis. Resveratrol (RES) possesses anti-tumor activity yet limited clinical value. Valproic acid (VPA), a histone deacetylase inhibitor, boosts multiple anti-cancer drugs' efficacy. This study explored RES/VPA synergy in glioma cell lines and syngeneic mouse tumors, and confirmed the reactive oxygen species (ROS)-programmed cell death protein 4 (PDCD4)-Bax cascade drives combined pro-apoptotic and anti-invasive effects. METHODS: CCK-8 detected cell proliferation; morphology and AO/EB staining assessed apoptosis. Wound healing and transwell assays measured migration. Western blot analyzed apoptosis and migration-related proteins, including PDCD4. Dihydroethidium staining tested intracellular ROS. Rescue assays used N-acetylcysteine (NAC) and PDCD4 knockdown; subcutaneous syngeneic mice validated in vivo anti-tumor activity. RESULTS: VPA alone exerted no significant cytotoxicity on glioma cells (p > 0.05 vs. NC), while RES inhibited U87MG and U251 cell proliferation in a concentration-dependent manner (p < 0.05, p < 0.01 vs. NC). RES/VPA co-treatment significantly enhanced cytotoxicity, suppressed migration and induced glioma cell apoptosis, with anti-tumor efficacy comparable to clinical doxorubicin (p > 0.05 Com vs. DOX; p < 0.01 Com vs. RES). Mechanistically, the combination markedly increased intracellular ROS accumulation (p < 0.001 Com vs. RES), upregulated PDCD4 expression (p < 0.01 Com vs. RES), and modulated apoptosis- and EMT-related protein levels to trigger cell apoptosis. NAC-mediated ROS scavenging or PDCD4 knockdown significantly abolished the synergistic pro-apoptotic effect of the combination therapy (p < 0.01 vs. Com), verifying the critical ROS-PDCD4 signaling function. In vivo, RES/VPA co-treatment significantly inhibited tumor growth (p < 0.01 Com vs. RES), and low-dose combination achieved equivalent efficacy to high-dose RES monotherapy (p > 0.05) without obvious toxic effects. CONCLUSION: RES combined with VPA exerts synergistic anti-glioma effects via the ROS-PDCD4-Bax signaling pathway, providing experimental evidence for VPA as an adjuvant in RES-based therapy. This combinatorial strategy overcomes the insufficient anti-tumor potency of RES monotherapy at the cellular and murine tumor level, expands the preclinical antitumor research value of natural polyphenols, and provides laboratory experimental reference for subsequent translational exploration of glioma therapy.