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

Abstract

AbstractDoxorubicin 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.