A novel combinatorial therapeutic strategy using resveratrol and viral oncolysis for diffuse intrinsic pontine glioma: an in vitro study

Pediatric central nervous system (CNS) tumors, specifically Diffuse Midline Gliomas (DMG) are a leading cause of cancer-related deaths in children presenting an unmet need for novel therapeutic development. In this study, we assessed the combined effects of resveratrol (RSV) and the oncolytic herpes simplex virus (oHSV), hrR3 in patient-derived diffuse intrinsic pontine glioma (DIPG) cell lines. RSV or hrR3 monotherapy resulted in a dose- and time-dependent reduction in cell viability. RSV pretreatment followed by hrR3 infection led to a significantly greater reduction in tumor cell viability than monotherapy. RSV pretreatment further enhanced the replication of hrR3, as evidenced by increased viral titers. Mechanistic analysis showed that the combination therapy was associated with reduced phosphorylation of the signal transducer and activator of transcription 3 (STAT3) and protein kinase B (AKT) signaling pathways, along with increased expression of apoptotic markers, including cleaved caspase-3 and Poly (ADP-ribose) polymerase (PARP). Together these findings indicate that RSV potentiates hrR3-mediated oncolysis in DIPG cells by enhancing viral replication, suppressing survival signaling and promoting apoptosis in DIPG cells in vitro. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-026-05029-x.