Chemosensitization effect of cerium oxide nanosheets by suppressing drug detoxification and efflux

Cerium oxide (CeO₂) nanomaterials (NMs) have wide applications in biomedicine and are also detected with increasing bioaccumulation in various biological and environmental media. Thus, a system was developed to evaluate the chemosensitization effect of CeO₂ NMs. Herein, we discovered that low doses of CeO₂ NMs could trigger reactive oxygen species (ROS) production and decrease mitochondrial membrane potential (MMP) without causing severe toxicity to cancer cells, while pretreatment of the cells with CeO₂ NMs enhanced the toxicity of the chemotherapeutic agent doxorubicin (DOX). The reduced efflux of DOX was mainly attributed to adenosine triphosphate (ATP) depletion, followed by attenuation of exocytosis and enhancement of DOX retention. Further investigations revealed that CeO₂ NM-induced ROS production caused depletion of intracellular glutathione (GSH) and consequent impairment of DOX detoxification. Moreover, CeO₂ NMs were found to enhance the chemosensitization of cancer cells rather than normal cells. Thus, this study uncovered the underlying application potential of CeO₂ NMs in cancer therapy by enhancing the efficacy of chemotherapeutic agent, which is associated with disruption of mitochondrial function and impairment of drug detoxification.