Zoledronic Acid and Leuprolide Acetate Affect Du-145 Migration towards Stem Cell Conditioned Medium

Abstract

Prostate cancer (PCa) is the most frequent genitourinary tumour and the third specific death cause, mostly because of bone metastasis. Currently, PCa is treated with GnRH analogues (leuprolide acetate-LA) and bisphosphonates (zoledronic acid-ZA) often in association. Thus, the aim of this work has been to study, in vitro, the effects of these drugs on cell line derived from PCa (DU-145). Particularly, we focused on some crucial aspects that drugs might play in tumor evolution and metastatization, by interfering with vitality, migration and interactions with bone cells. ZA cytotoxicity has been confirmed on DU-145 after 48-hours incubation at 5 μM, while LA cytotoxicity appears only after 72-hours contact at higher concentrations (100 μM). Both sub cytotoxic ZA and LA doses decreased 3D (transwell assay) PCa cell migration rate. pAkt/Akt ratio is diminished by LA and, even if less strikingly, by ZA, in agreement with the respective inhibition migration ratios. Cells underwent migration test in mesenchymal stem cells – MSC – conditioned medium (MSC-CM), which significantly increases the rate of migration (210%± 2.2; P<0.05). Addition of both ZA and LA quenched the attractive effect of conditioned medium. Our results suggest that LA and, mostly, ZA have a direct toxic effect on cancer cells. Furthermore, they inhibit cellular migration even under attractive stimuli exerted by MSC, and this might contribute to explain their effect in limiting metastatization.