Prostate Cancer Cells Are Sensitive to Lysosomotropic Agent Siramesine through Generation Reactive Oxygen Species and in Combination with Tyrosine Kinase Inhibitors

SIMPLE SUMMARY: Advanced prostate cancer is often drug resistant and requires new treatment strategies. Lysosomoptropic agents selectively target lysosomes in cancer cells leading to cell death. We found that the lysosome-targeted drug, siramesine, induced cell death in prostate cancer cells lines through lipid peroxidation and, in combination with the kinase inhibitor lapatinib, increases cell death. This provides a novel strategy to treat aggressive prostate cancer cells. ABSTRACT: Background: Prostate cancer is the most common cancer affecting men often resulting in aggressive tumors with poor prognosis. Even with new treatment strategies, drug resistance often occurs in advanced prostate cancers. 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 lysosomotropic agents with targeted inhibitors can induce increased cell death in different cancer types, but prostate cancer cells have not been investigated. Methods: We treated prostate cancer cells with lysosomotropic agents and determine their cytotoxicity, lysosome membrane permeabilization (LMP), reactive oxygen species (ROS) levels, and mitochondrial dysfunction. In addition, we treated cells with lysosomotropic agent in combination with tyrosine kinase inhibitor, lapatinib, and determined cell death, and the role of ROS in this cell death. Results: Herein, we found that siramesine was the most effective lysosomotropic agent at inducing LMP, increasing ROS, and inducing cell death in three different prostate cancer cell lines. Siramesine was also effective at increasing cell death in combination with the tyrosine kinase inhibitor, lapatinib. This increase in cell death was mediated by lysosome membrane permeabilization, an increased in ROS levels, loss of mitochondrial membrane potential and increase in mitochondrial ROS levels. The combination of siramesine and lapatinib induced apoptosis, cleavage of PARP and decreased expression of Bcl-2 family member Mcl-1. Furthermore, lipid peroxidation occurred with siramesine treatment alone or in combination with lapatinib. Treating cells with the lipid peroxidation inhibitor alpha-tocopherol resulted in reduced siramesine induced cell death alone or in combination with lapatinib. The combination of siramesine and lapatinib failed to increase cell death responses in normal prostate epithelial cells. Conclusions: This suggests that lysomotropic agents such as siramesine in combination with tyrosine kinase inhibitors induces cell death mediated by ROS and could be an effective treatment strategy in advanced prostate cancer.