The lysosomotropic agent siramesine and the tyrosine kinase inhibitor lapatinib induce cell death in prostate cancer cells

Abstract

Prostate cancer is the most common cancer affecting men often resulting in aggressive tumors with poor prognosis. Novel therapeutic strategies to treat prostate cancer include combinational treatments aiming to reduce the negative effects of chemotherapy, such as drug resistance. The use of lysosomotropic agents offers a new treatment possibility since they disrupt lysosomal membranes and can trigger a series of events leading to cell death. In addition, combining lysosome disrupting agents with targeted inhibitors can induce synergistic cell death in different cancer types. In prostate cancer, these combination treatments have not been tested before. I found the lysosomotropic siramesine and the tyrosine kinase inhibitor lapatinib to be the most potent drug combination to induce cell death. I also investigated the mechanism by which cells were dying by siramesine and lapatinib treatment and found that increases in ROS caused significant cellular damage leading to mitochondrial dysfunction and high levels of lipid peroxidation. These effects were more prominent in PC3 cells, which are representative of the most aggressive type of the disease and therefore, this combination holds the potential to treat advanced prostate cancer.