Ultrasound-mediated mechanical force perturbing plasma membrane properties for paclitaxel-resistant epithelial ovarian cancer therapy

Abstract Paclitaxel (PTX) resistance in epithelial ovarian cancer (EOC) is a significant clinical challenge, often resulting in cross-resistance to other chemotherapeutic agents and contributing to a low five-year survival rate. In recent years, the physical characteristics of tumor cells have been found to play a critical role in the development of resistance, particularly the plasma membrane, which is responsible for sensing and transmitting mechanical signals. As low-intensity focused ultrasound with microbubbles (LIFU-MB) treatment can modulate the physical characteristics of plasma membrane, this study explored its potential for treating PTX-resistant EOC. Results demonstrated that LIFU-MB treatment decreased plasma membrane fluidity and made membrane potential less negative in PTX-resistant ovarian cancer cells, likely due to reduced levels of negatively charged phosphatidylserine. The disruption of plasma membrane properties by ultrasound-triggered mechanobiological forces affected the expression and function of the transmembrane protein SLC7A11, ultimately leading to ferroptosis of PTX-resistant ovarian cancer cells. In the in vivo study, tumor volumes in nude mice were significantly reduced in the LIFU-MB treatment group, with no apparent systemic or organ-specific toxicity. Overall, our findings establish ultrasound-triggered mechanobiological forces as a potential and innovative therapeutic strategy for PTX-resistant EOC, exerting their antitumor effects by reprogramming membrane biophysical properties and triggering ferroptotic cell death, thereby offering a promising avenue for overcoming chemoresistance.