Sonocavitation-Induced Mitochondrial Dysfunction via ROS-Mediated Apoptosis for Paclitaxel-Resistant Ovarian Cancer Therapy
To investigate whether sonocavitation, induced by low-intensity focused ultrasound combined with microbubbles, can overcome paclitaxel resistance in ovarian cancer by promoting apoptosis through reactive oxygen species (ROS)-mediated mitochondrial dysfunction. Paclitaxel-resistant ovarian cancer tissues and cell lines were compared with chemotherapy-sensitive counterparts for the expression of apoptosis-related proteins. Sonocavitation treatment was applied to resistant cells using optimized ultrasound parameters. Apoptosis, ROS production, mitochondrial morphology, oxygen consumption, mitochondrial membrane potential and mitochondrial membrane proteins were evaluated by flow cytometry, transmission electron microscopy, oxygen consumption assays, adenosine triphosphate (ATP) measurements, mitochondrial membrane potential assay kit staining and Western blotting. In vivo antitumor efficacy and biosafety were examined in paclitaxel-resistant xenograft mouse models, with tumor growth curves, survival analysis, and hematological/organ histology assessments. Paclitaxel-resistant ovarian cancer tissues exhibited elevated Bcl-2 and reduced Bax and Caspase-3, indicating impaired intrinsic apoptosis. Sonocavitation significantly increased apoptosis in resistant ovarian cancer cells and induced marked mitochondrial dysfunction, including reduced mitochondrial size, disrupted oxygen consumption, decreased ATP levels, collapse of mitochondrial membrane potential and destruction of mitochondrial membrane proteins. Cytochrome c release and activation of cleaved Caspase-3 confirmed mitochondrial-dependent apoptosis. In vivo, sonocavitation suppressed tumor growth and prolonged survival without causing systemic toxicity. ROS scavengers partially reversed these effects, confirming that ROS accumulation is a key mediator of the therapeutic mechanism. Sonocavitation induces apoptosis in paclitaxel-resistant ovarian cancer through ROS-mediated mitochondrial dysfunction and demonstrates effective tumor-suppressive activity with a favorable safety profile. These findings support sonocavitation as a promising adjuvant strategy to overcome chemoresistance and enhance ovarian cancer treatment outcomes.