Abstract

Background 5-Aminolevulinic acid photodynamic therapy (ALA-PDT) is a promising treatment for glioblastoma multiforme (GBM), the most malignant form of brain cancer. However, challenges persist. The heterogeneous and invasive nature of GBM frequently results in hypoxic regions within the tumor and its periphery, where the efficacy of PDT may be diminished. Consequently, it is imperative to explore combination treatments that enhance PDT-induced cell death. Resveratrol (Res) is a natural phenolic compound recognized for its anti-inflammatory and anti-tumor properties against glioblastoma cells. Given these considerations, the study employed sublethal-dose ALA-PDT to simulate the reduced efficacy of ALA-PDT commonly observed in GBM and explored the effects of combining Res with sublethal-dose ALA-PDT on glioblastoma cells in vitro. Methods Human glioblastoma U251 and U87 cells were treated with Res and/or sublethal-dose ALA-PDT. Cell viability, migration inhibition, and apoptosis were assessed using the CCK-8 assay, colony-forming assay, scratch assay, Calcein-AM/PI, and TUNEL staining. Western blotting was performed to detect the expression levels of proteins involved in the ERK1/2 and mTOR signaling pathways and autophagy. Results Res inhibited the viability of U251 and U87 cells in a dose- and incubation time-dependent manner. Compared to single treatments, the combination of sublethal-dose ALA-PDT and Res reduced cell viability and migration and induced apoptosis. This combined treatment suppressed the ERK1/2 and mTOR signaling pathways. Additionally, Res enhanced ALA-PDT-induced autophagy-dependent cell death, as autophagy inhibitors partially reversed the decrease in cell viability resulting from the combined treatment. Conclusion This study demonstrates that the combination of Res and ALA-PDT enhances the inhibition of glioblastoma cell growth compared to the single treatments. The combined therapy can induce apoptosis and autophagy in GBM cells by suppressing