Photodynamic therapy enhances the cytotoxicity of temozolomide against glioblastoma via reprogramming anaerobic glycolysis

Abstract

The successful application of photodynamic therapy in the treatment of glioma (CNS WHO grade 4) depends in large part to the effect of killing cells in the infiltrating area after tumor had been removed, when combined with radiotherapy, chemotherapy, and targeted drug therapy. The purpose of this study was to investigate the potential mechanism of TMZ's involvement in the glioma's glycolytic metabolic pathway during photodynamic therapy. The low dose of photodynamic therapy treatment on the cell viability of gliomas was investigated by CCK8. Alterations in reactive oxygen species were detected by flow cytometer. The differentially expressed proteins related to glucose transporter 1 (GLUT-1), matrix metalloproteinase-2 (MMP-2)/actively MMP-2 and apoptosis-associated caspase-3/cleaved caspase-3 were evaluated by Western Blot experiment. Additionally, transmission electron microscopy observed apoptosis, necrosis and the changes of the ultrastructure in U251 cells. In addition, antitumor effects in vivo were tested using orthotopic BALB/c mice with the glioma U87 model. The findings showed that low dose PDT affected mitochondrial function by inducing radical oxygen, hindered cellular glucose transport and metabolism, and induced apoptosis. The results also showed that cell viability considerably decreased and increased cell apoptosis under the PDT therapy. The HIF-1/GLUT-1 axis enhanced the cytotoxicity of temozolomide in gliomas as a result of PDT treatment, which was influenced by ROS. As a result, this study presents PDT as a potential therapeutic approach for treating malignant glioma, and enhanced antitumor effect of TMZ by inhibiting glycolytic pathway.