In multiple myeloma, the overexpression of receptor activator of nuclear factor kappa B (NF-jB) ligand (RANKL) leads to the induction of NF-jB and activator protein-1 (AP-1)-related osteoclast activation and enhanced bone resorption. The purpose of this study was to examine the molecular and functional effects of proteasome inhibition in RANKL-induced osteoclastogenesis. Furthermore, we aimed to compare the outcome of proteasome versus selective NF-jB inhibition using bortezomib (PS-341) and I-jB kinase inhibitor PS-1145. Primary human osteoclasts were derived from CD14 þ precursors in presence of RANKL and macrophage colony-stimulating factor (M-CSF). Both bortezomib and PS-1145 inhibited osteoclast differentiation in a dose-and time-dependent manner and furthermore, the bone resorption activity of osteoclasts. The mechanisms of action involved in early osteoclast differentiation were found to be related to the inhibition of p38 mitogenactivated protein kinase pathways, whereas the later phase of differentiation and activation occurred due to inhibition of p38, AP-1 and NF-jB activation. The AP-1 blockade contributed to significant reduction of osteoclastic vascular endothelial growth factor production. In conclusion, our data demonstrate that proteasomal inhibition should be considered as a novel therapeutic option of cancer-induced lytic bone disease.
This manuscript is the first report that describes the effects of curcumin toward human osteoclastogenesis, and builds the framework for clinical trials of curcumin in the treatment of cancer-induced lytic bone disease.
Proteasome inhibitors represent novel anti-cancer drugs which interact with the proteasome-ubiquitin pathway. The 26S proteasome is a multicatalytic threonine protease with three distinct catalytic activities. It is responsible for intracellular protein turnover in eukaryotic cells, including the processing and degradation of short- and some long-living proteins required for regulation of various cellular functions. Subsequently, the inhibition of the proteasomal function results in stabilization and accumulation of its substrates, which notably include cyclins, cyclin-dependent kinase inhibitors, transcriptional factors, tumor suppressor proteins and proto-oncogenes. This results in confounding signals in the cell inducing cell cycle arrest and activation of apoptotic programs. Acting on transcriptional factor NF-kappaB, which is upregulated in some tumors undergoing chemotherapy or irradiation and downregulated by proteasome inhibition, a significant chemosensitization and consequently synergistic effects concerning the anti-tumor activity could be achieved. Bortezomib is the first proteasome inhibitor that has entered clinical trials. In multiple myeloma, both the US Food and Drug Administration and European Medicine Evaluation Agency granted approval for the use of bortezomib (Velcade) for the treatment of multiple myeloma patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy. At present, other trials examine the activity in a variety of solid tumors and hematological malignancies. This paper reviews preclinical and clinical results.
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