Contribution of Oxidative Stress Induced by Sonodynamic Therapy to the Calcium Homeostasis Imbalance Enhances Macrophage Infiltration in Glioma Cells

SIMPLE SUMMARY: Sonodynamic therapy (SDT) is a non-invasive technique that is based on the combination of a sonosensitizer and acoustic activation that destroys the mitochondrial respiratory chain, leading to increases in the levels of intracellular reactive oxygen species (ROS) and calcium overload as well as to the inhibition of proliferation, invasion, and promotion of the apoptosis of biologically more aggressive grade 4 glioma. This study aimed to better understand the calcium overload mechanism involved in SDT irradiation and killing gliomas as well as in lipid metabolism in aggressive glioma cells under the SDT treatment. In this study, we examined the hypothesis that the early application of the mechanosensitive Ca(2+) channel Piezo1 antagonist (GsMTx4) could better promote the dissociation and polymerization of the Ca(2+) lipid complex and further increase oxidative stress levels, leading to a better anti-tumor effect when SDT was used as a treatment. Moreover, Piezo1’s early closing state and intracellular calcium overload formation may be a key link that leads to the final tumor-infiltrating macrophages. ABSTRACT: Background: To better understand the Ca(2+) overload mechanism of SDT killing gliomas, we examined the hypothesis that the early application of the mechanosensitive Ca(2+) channel Piezo1 antagonist (GsMTx4) could have a better anti-tumor effect. Methods: The in vitro effect of low-energy SDT combined with GsMTx4 or agonist Yoda 1 on both the ROS-induced distribution of Ca(2+) as well as on the opening of Piezo1 and the dissociation and polymerization of the Ca(2+) lipid complex were assessed. The same groups were also studied to determine their effects on both tumor-bearing BALB/c-nude and C57BL/6 intracranial tumors, and their effects on the tumor-infiltrating macrophages were studied as well. Results: It was determined that ultrasound-activated Piezo1 contributes to the course of intracellular Ca(2+) overload, which mediates macrophages (M1 and M2) infiltrating under the oxidative stress caused by SDT. Moreover, we explored the effects of SDT based on the dissociation of the Ca(2+) lipid complex by inhibiting the expression of fatty acid binding protein 4 (FABP4). The Piezo1 channel was blocked early and combined with SDT treatment, recruited macrophages in the orthotopic transplantation glioma model. Conclusions: SDT regulates intracellular Ca(2+) signals by upregulating Piezo1 leading to the inhibition of the energy supply from lipid and recruitment of macrophages. Therefore, intervening with the function of the Ca(2+) channel on the glioma cell membrane in advance is likely to be the key factor to obtain a better effect combined with SDT treatment.