Investigating the Effect of Lapatinib on the Performance of Sonodynamic Therapy Against Prostate Cancer via Inhibition of the ABCG2 Efflux System

Sonodynamic therapy (SDT) is an emerging site specific and minimally-invasive modality for cancer treatment. Its efficacy heavily relies on the accumulation and retention of systemically-administered sensitizing agents within tumor cells. Active molecular efflux via membrane transporters, such as the human ATP-binding cassette (ABC) superfamily G member 2 (ABCG2) transporter, can pose a major challenge by reducing intracellular levels of sensitizers and hinder sonodynamic activity. In this study, the role of ABCG2 transporter in the retention of nanoparticulate hematoporphyrin was investigated using prostate cancer cells. The potential of lapatinib to improve cellular retention of the sensitizer via inhibition of ABCG2 and improve the efficacy of SDT was evaluated. The effect of hypoxia and neuroendocrine differentiation on ABCG2 activity and the role of lapatinib were examined. Results showed that hypoxia intensifies ABCG2 localization in the cytoplasmic membrane. There was no effect of lapatinib on the cellular accumulation of nanoparticulate hematoporphyrin during exposure of the cell systems to the sensitizer. Following sensitizer withdrawal, a sharp intracellular hematoporphyrin level decrease was observed within the first 2 h. Lapatinib significantly attenuated the reduction of intracellular sensitizer in hypoxia, during the first 8 h after withdrawal of the sensitizer. Lapatinib can extend the intracellular presence of the sonosensitizer, prolonging the therapeutic window for performing SDT. This outcome underlined the value of lapatinib for improving the sensitizer intracellular levels in hypoxic areas of the tumor mass, where sensitizer supply is expected to be low, due to the low vascularization levels.