Prostate cancer (PCa) is the most common cancer in men, and up to 70-80% of patients with advanced disease present with bone metastases. Current treatment options for metastasised PCa are not curative since hormone, chemo-, and radiation-therapy are relatively ineffective in targeting PCa cells with stem/progenitor-like characteristics (CSCs). Salinomycin, an antibiotic used in poultry, was previously identified in a high through-put screen to target breast CSCs 100x more effectively than paclitaxel. In this study we investigated the anti-tumour effects of salinomycin in human PCa cells in vitro, in vivo and ex vivo. Salinomycin dose-dependently inhibited the proliferation of various human PCa cells (PC3, PC-3M-Pro4, DU145, C4-2B, PC339, PC346C). Interestingly, after establishing docetaxel-resistant cells by serial passaging in vivo (PC339-DOC), salinomycin differentially affected docetaxel-resistant cells (vs. parental). Salinomycin induced apoptosis as determined by flow cytometry (Ann/PI) and immunohistochemistry (caspase-3), reduced Notch-signalling (RBPkJ/Luc reporter assay) and inhibited migration of PC-3M-Pro4 cells. When PC-3M-Pro4 cells were FACS-sorted for high aldehyde dehydrogenase (ALDH) enzymatic activity, salinomycin inhibited the clonogenic and sphere-forming capacity of both CSC and non-CSCs equally well. Salinomycin pretreatment of PC-3M-Pro4/mCherry completely blocked extravasation and metastatic colonisation in a zebrafish model with a GFP+ vasculature in which cells were intravascularly injected. Salinomycin pretreatment of PC-3M-Pro4/luc2 cells also reduced the formation of distant metastases in a bone metastasis model of intracardiac injection of cancer cells in nude mice. Ex vivo, salinomycin treatment for 7 days (vs. vehicle treated) strongly reduced the number of PCa cells in a novel near-patient model of culturing prostate tumor slices from transurethral resection of prostate cancer tissue (TURP) and bone metastases. In conclusion, salinomycin is effective in inhibiting PCa growth in vitro, in vivo and in near-patients ex vivo models. Therefore, salinomycin may be a promising novel therapeutic approach for the treatment of advanced, bone metastatic PCa.
Disclosure: The authors declared no competing interests. This study was supported by the Netherlands Organization for Scientific Research (NWO, VENI-Grant, 916.131.10).