Cabozantinib targets bone microenvironment modulating human osteoclast and osteoblast functions
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Marco Fioramonti1,*, Daniele Santini1,*, Michele Iuliani1, Giulia Ribelli1, Paolo Manca1, Nicola Papapietro2, Filippo Spiezia2, Bruno Vincenzi1, Vincenzo Denaro2, Antonio Russo3, Giuseppe Tonini1, Francesco Pantano1
1Department of Medical Oncology, Campus Bio-Medico University of Rome, Rome, Italy
2Department of Orthopaedics and Trauma Surgery, University Campus Bio-Medico of Rome, Rome, Italy
3Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
*These authors share first authorship and are listed in alphabetical order
Michele Iuliani, email: [email protected]
Keywords: cabozantinib, bone microenvironment, receptor activator of nuclear factor-kb ligand (RANKL), osteoprotegerin (OPG), human primary cells
Received: November 25, 2016 Accepted: January 22, 2017 Published: February 16, 2017
Cabozantinib, a c-MET and vascular endothelial growth factor receptor 2 inhibitor, demonstrated to prolong progression free survival and improve skeletal disease-related endpoints in castration-resistant prostate cancer and in metastatic renal carcinoma. Our purpose is to investigate the direct effect of cabozantinib on bone microenvironment using a total human model of primary osteoclasts and osteoblasts.
Osteoclasts were differentiated from monocytes isolated from healthy donors; osteoblasts were derived from human mesenchymal stem cells obtained from bone fragments of orthopedic surgery patients. Osteoclast activity was evaluated by tartrate resistant acid phosphatase (TRAP) staining and bone resorption assays and osteoblast differentiation was detected by alkaline phosphatase and alizarin red staining.
Our results show that non-cytotoxic doses of cabozantinib significantly inhibit osteoclast differentiation (p=0.0145) and bone resorption activity (p=0.0252). Moreover, cabozantinib down-modulates the expression of osteoclast marker genes, TRAP (p=0.006), CATHEPSIN K (p=0.004) and Receptor Activator of Nuclear Factor k B (RANK) (p=0.001). Cabozantinib treatment has no effect on osteoblast viability or differentiation, but increases osteoprotegerin mRNA (p=0.015) and protein levels (p=0.004) and down-modulates Receptor Activator of Nuclear Factor k B Ligand (RANKL) at both mRNA (p<0.001) and protein levels (p=0.043). Direct cell-to-cell contact between cabozantinib pre-treated osteoblasts and untreated osteoclasts confirmed the indirect anti-resorptive effect of cabozantinib.
We demonstrate that cabozantinib inhibits osteoclast functions “directly” and “indirectly” reducing the RANKL/osteoprotegerin ratio in osteoblasts.
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