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

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