Low-dose arsenic trioxide enhances 5-aminolevulinic acid-induced PpIX accumulation and efficacy of photodynamic therapy in human glioma

• The enhancement of 5-ALA-induced PpIX accumulation in glioma cells can be successfully achieved with low-dose arsenic trioxide.
• The same concentration of arsenic trioxide does not influence the PpIX levels in rat normal cortex astrocytes.
• Low-dose arsenic trioxide increases the efficacy of 5-ALA induced PDT in glioma cells.
• The expression of CPOX was upregulated in glioma cells after treatment with arsenic trioxide.

Among glioma treatment strategies, 5-aminolevulinic acid (5-ALA)-based fluorescence-guided resection (FGR) and photodynamic therapy (PDT) have been used as effective novel approaches against malignant glioma. However, insufficient intracellular protoporphyrin IX (PpIX) accumulation limits the application of FGR and PDT in the marginal areas of gliomas. To overcome these issues, we assessed the intracellular levels of PpIX in human glioma cell lines and rat cortical astrocytes pretreated with 0.1 μM arsenic trioxide (ATO). Apoptosis and cell viability after PDT were evaluated using Annexin V-FITC apoptosis detection kit and MTT assay, respectively. In order to find out the possible mechanism, we investigated the expression of the key enzymes in the heme biosynthesis pathway, which regulates porphyrin synthesis in glioma cells. Our findings showed that the 5-ALA-induced PpIX accumulation in glioma cell lines pretreated with 0.1 μM ATO was increased relative to the control groups. No changes in fluorescence intensity were detected in the rat cortical astrocytes pretreated using the same ATO concentration. Apoptosis following PDT in glioma cells pretreated with 0.1 μM ATO were significantly higher than in control groups, especially late apoptotic cells, while the cell viability was decreased. The expression of CPOX was upregulated in glioma cells after pretreatment with 0.1 μM ATO. We concluded that ATO was a potential optional approach in enhancing intracellular PpIX accumulation and improving the benefits of 5-ALA-induced FGR and PDT in glioma.