Background: Abiraterone acetate (ABI) is associated not only with a significant survival advantage in both chemotherapy-naive and -treated patients with metastatic castration-resistant prostate cancer (mCRPC), but also with a reduced pain from skeletal metastases, a delay in time to development of Skeletal Related Events (SREs) and in radiological skeletal progression. These bone benefits may be related to a direct effect on prostate cancer cells in bone or to a specific mechanism directed to bone microenvironment. To test this hypothesis we have designed an in vitro study aimed to evaluate a potential direct effect of ABI on human primary osteoclasts/osteoblasts (OCL/OBL) cultured with/without steroids.
Methods: Primary OCL were differentiated from human monocyte; primary OBL were obtained from mesenchymal stem cells. OCL differentiation and activity were evaluated by TRAP and Bone Resorption assays; OBL differentiation was analysed by ALP and Alizarin Red assays.
Results: Our results showed that non-cytotoxic doses of ABI (5 μM/10 μM) have a statistically significant inhibitory effect on OCL differentiation (P<0.001) and bone resorption activity (P<0.001) with or without steroids. Moreover, we found that ABI down-modulated the expression of OCL marker genes: TRAP (P<0.001), CATHEPSIN K (P<0.001), METALLOPROTEINASE-9 (P=0.001). Furthermore ABI strongly promoted OBL differentiation (P=0.02) and increased bone matrix deposition (P=0.014) in presence/absence of steroids. Finally ABI showed a significant up-regulation of OBL specific genes ALP (P=0.015) and OSTEOCALCIN (P=0.034). The reduction of CATHEPSIN K levels and the increase of OSTEOCALCIN expression were confirmed by western blot.
Conclusions: Overall, these findings represent the first evidence of a novel biological mechanism of ABI consisting in a direct bone anabolic and an anti-resorptive activity. These data may explain, together with the known antitumoural effect on CRPC cells, the high efficacy of ABI treatment in improving multiple skeletal disease specific clinical endpoints (time to SRE, bone rPFS, pain from bone metastases).
Disclosure: The authors declared no competing interests.