TP53 Genotype-Dependent Cellular Responses to DVDMS-Sonodynamic Therapy in Oral Squamous Cell Carcinoma

This study aimed to assess the inhibitory effects and underlying mechanisms of sonodynamic therapy (SDT) mediated by the novel sonosensitizer sinoporphyrin sodium (DVDMS) in oral squamous cell carcinoma (OSCC) cells exhibiting distinct TP53 genotypes.

Cytotoxicity, intracellular uptake and localization of DVDMS, reactive oxygen species (ROS) levels, apoptosis and autophagy were assessed in two OSCC cell lines (SAS and HSC-3). Expression levels of p53, Bax, Bcl-2 and LC3B proteins were analyzed. The p53 inhibitor pifithrin-α (PFT-α) was utilized to determine its modulatory effects on SDT-induced cellular responses in SAS cells.

DVDMS-mediated SDT significantly inhibited cell proliferation in both SAS and HSC-3 lines. DVDMS predominantly accumulated in the mitochondria, with higher colocalization observed in SAS cells. SDT induced a marked elevation in intracellular ROS and mitochondrial apoptosis, particularly in SAS cells. After 2 h of SDT, there was a significant decrease in autophagic activity in SAS cells, whereas an increase was noted in HSC-3 cells. In SAS cells, SDT resulted in significant upregulation and nucleocytoplasmic translocation of p53 protein. Treatment with PFT-α partially attenuated apoptosis, reversed autophagy inhibition and suppressed p53 translocation in SAS cells.

DVDMS-mediated SDT elicited greater cytotoxic responses in OSCC cells harboring wild-type TP53 (SAS) compared to mutant TP53 (HSC-3) cells. The therapy induced mitochondrial apoptosis and modulated autophagy in both cell lines, with more pronounced responses observed in wild-type TP53 cells. These findings suggest that p53 plays a critical regulatory role in mediating SDT-induced mitochondrial apoptosis and autophagy under DVDMS sensitization in OSCC.