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

Abstract

Background: To better understand the Ca2+ overload mechanism of SDT killing gliomas, we examined the hypothesis that the early application of the mechanosensitive Ca2+ 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 Ca2+ as well as on the opening of Piezo1 and the dissociation and polymerization of the Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ channel on the glioma cell membrane in advance is likely to be the key factor to obtain a better effect combined with SDT treatment.