Enhancing Sonodynamic Therapy in Prostate Cancer: Cavitation-Induced Cytotoxicity and Mitochondrial Unfolded Protein Response Disruption

Abstract

Prostate cancer remains a significant health challenge, necessitating more effective and targeted treatment strategies. Sonodynamic therapy (SDT) is a promising, non-invasive approach that utilizes ultrasound-activated sensitizers to induce cancer cell death. However, the role of ultrasound cavitation in enhancing SDT efficacy and its effects on mitochondrial stress responses remain unclear. We hypothesized that increasing cavitation density through optimized ultrasound parameters would enhance Ce6-mediated SDT effectiveness by increasing cytotoxicity, reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP) loss, and disrupting the mitochondrial unfolded protein response (mtUPR). Prostate cancer cells were treated with Ce6 and exposed to ultrasound with varying duty cycles (50% and 100%) and power intensities (0.5 W/cm², 1 W/cm², and 1.5 W/cm²). Cavitation density was measured, and its effects on cell viability, ROS levels, MMP disruption, and mtUPR mediator expression, including activating transcription factor 5 (ATF5), heat shock protein 60 (HSP60), and caseinolytic protease proteolytic subunit (CLPP), were analyzed at protein and mRNA levels. Higher duty cycles significantly increased cavitation density, leading to enhanced cytotoxicity, elevated ROS generation, and greater MMP loss in Ce6-mediated SDT. Additionally, SDT reduced mtUPR mediator expression, with cavitation further amplifying these effects. These findings suggest that cavitation-enhanced SDT may contribute to improved therapeutic efficacy in prostate cancer treatment by modulating mitochondrial stress responses and affecting cell viability. Optimizing ultrasound parameters to maximize cavitation effects may contribute to the development of more effective SDT-based cancer therapies.