Endocrine Abstracts

Prostate cancer (PCa) is the most common tumor pathology in men worldwide. The medical treatments currently used as first-line therapy after surgery are anti-androgens like abiraterone or enzalutamide, which, unfortunately, fail to stop the disease in a high percentage of cases, resulting in progression towards aggressive castration-resistant PCa. Therefore, new therapeutic tools to manage PCa are urgently needed. Biguanides and statins, two types of drugs commonly used in metabolism-related pathologies (i.e. type 2 diabetes, hypercholesterolemia and obesity) have been recently shown to exert antitumoral actions in several cancers. Here, we aimed to determine the antitumoral capacity of biguanides, statins and their combination in human PCa cells. To that end, different biguanides [metformin (5 mM), buformin and phenformin (1 mM)], statins [atorvastatin, simvastatin and lovastatin (10 μM)] and selected combinations were tested in PCa-derived cell-lines (22RV1, LNCaP, PC3 and DU145), in the normal prostate cell-line (RWPE-1), and in normal primary prostate cell-cultures obtained from healthy donors, by using different functional assays (i.e. cell proliferation, migration, tumorosphere formation, clonogenic assay, etc). Results revealed that all biguanides and statins reduced cell proliferation at 48- and 72-h in all the PCa cell lines tested (except statins in DU145 cells), being the effect of phenformin and simvastatin significantly higher compared with metformin/buformin and atorvastatin/lovastatin, respectively, in most of the PCa cell-lines. Interestingly, the combination of metformin with atorvastatin or simvastatin exerted a synergistic inhibitory effect on cell proliferation. Of note, the inhibitory effect caused by biguanides, statins or their combination in cell proliferation was significantly less pronounced in normal prostate cells (RWPE-1 and primary cell cultures) compared to that observed in PCa cell lines. In addition, metformin, simvastatin and its combination significantly reduced cell migration in all PCa cell-lines, being this effect additive when both compounds were co-administrated in LNCaP and DU145 cell-lines. Furthermore, the strong antitumoral effect of biguanides and statins observed in PCa cells was reinforced with the results showing that combined treatment with both compounds inhibited tumorosphere and colony formation. Altogether, our results revealed that biguanides and statins are able to reduce tumor aggressiveness in vitro, being this effect significantly higher when these compounds are combined, suggesting a potential therapeutic role of these compounds, especially their combination, for the treatment of PCa.