Sonodynamic Treatment Triggers Cancer Cell Killing by Doxorubicin in P‐Glycoprotein‐Mediated Multidrug Resistant Cancer Models

Doxorubicin is a widely used chemotherapeutic agent that can be hampered in its efficacy by the occurrence of multidrug resistance (MDR), due to the overexpression of the drug efflux transporter P-glycoprotein. As overcoming MDR still remains an unmet clinical need, this work aims at investigating an innovative strategy. Sonodynamic therapy (SDT) selectively kills cancer cells by combining low-intensity ultrasound (US) with a responsive chemical agent (sonosensitiser) that can be activated to produce reactive oxygen species (ROS). Therefore, the efficacy of SDT, using doxorubicin as sonosensitiser, is studied on human MDR ovarian (A2780/MDR) and colon (HT-29/MDR) cancer cells. The ultrasound exposure of MDR cells pre-incubated with non-cytotoxic concentrations of doxorubicin for 1 h has induced a statistically significant decrease of cell proliferation after 72 h. Interestingly, US has selectively triggered the ROS-mediated cytotoxicity of the doxorubicin entrapped into the cancer cell membrane leading to necrotic cancer cell death by lipid peroxidation. Moving from 2D to 3D HT-29/MDR cell cultures, the ability of SDT to reduce the growth of MDR spheroids by inducing significant necrotic cancer cell death is also confirmed. In conclusion, SDT can have a role in treating MDR tumors by eliciting the ROS-mediated cytotoxicity of doxorubicin.