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 delay in time to development of Skeletal Related Events 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 designed an in vitro study aimed to evaluate a potential direct effect of ABI on human primary osteoclasts/osteoblasts (OCLs/OBLs). We also assessed changes in bone turnover markers, serum carboxy-terminal collagen crosslinks (CTX) and alkaline phosphatase (ALP), in 49 mCRPC patients treated with ABI.Our results showed that non-cytotoxic doses of ABI have a statistically significant inhibitory effect on OCL differentiation and activity inducing a down-modulation of OCL marker genes TRAP, cathepsin K and metalloproteinase-9. Furthermore ABI promoted OBL differentiation and bone matrix deposition up-regulating OBL specific genes, ALP and osteocalcin. Finally, we observed a significant decrease of serum CTX values and an increase of ALP in ABI-treated patients.These findings suggest a novel biological mechanism of action of ABI consisting in a direct bone anabolic and anti-resorptive activity.

Biological and clinical effects of abiraterone on anti-resorptive and anabolic activity in bone microenvironment

BUTTIGLIERO, CONSUELO;BERTAGLIA, VALENTINA;TUCCI, Marcello;VIGNANI, FRANCESCA;BERRUTI, Alfredo;SCAGLIOTTI, Giorgio Vittorio;
2015

Abstract

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 delay in time to development of Skeletal Related Events 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 designed an in vitro study aimed to evaluate a potential direct effect of ABI on human primary osteoclasts/osteoblasts (OCLs/OBLs). We also assessed changes in bone turnover markers, serum carboxy-terminal collagen crosslinks (CTX) and alkaline phosphatase (ALP), in 49 mCRPC patients treated with ABI.Our results showed that non-cytotoxic doses of ABI have a statistically significant inhibitory effect on OCL differentiation and activity inducing a down-modulation of OCL marker genes TRAP, cathepsin K and metalloproteinase-9. Furthermore ABI promoted OBL differentiation and bone matrix deposition up-regulating OBL specific genes, ALP and osteocalcin. Finally, we observed a significant decrease of serum CTX values and an increase of ALP in ABI-treated patients.These findings suggest a novel biological mechanism of action of ABI consisting in a direct bone anabolic and anti-resorptive activity.
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abiraterone acetate; bone marker; osteoblast; osteoclast; Alkaline Phosphatase; Androstenes; Antineoplastic Agents; Blotting, Western; Bone Remodeling; Bone and Bones; Cell Differentiation; Collagen Type I; Enzyme-Linked Immunosorbent Assay; Humans; Male; Osteoblasts; Osteoclasts; Peptides; Prostatic Neoplasms, Castration-Resistant; Real-Time Polymerase Chain Reaction; Transcriptome
Iuliani, Michele; Pantano, Francesco; Buttigliero, Consuelo; Fioramonti, Marco; Bertaglia, Valentina; Vincenzi, Bruno; Zoccoli, Alice; Ribelli, Giulia; Tucci, Marcello; Vignani, Francesca; Berruti, Alfredo; Scagliotti, Giorgio Vittorio; Tonini, Giuseppe; Santini, Daniele
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1564897
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