Effects of proteasome inhibitors on bone cancer

Abstract

Bone metastasis is a frequent complication of cancer, occurring in up to 70% of patients with advanced breast or prostate cancer, while bone disease is also the characteristic clinical feature of multiple myeloma. Skeletal-related events can be devastating, with major effect on the quality of life and survival. Bisphosphonates are the mainstay of therapeutic management of bone disease of solid tumors and myeloma, and denosumab has recently been approved for patients with bone metastases. Both act through inhibition of the osteoclast activity but do not restore bone formation. Proteasome inhibition has direct bone anabolic effects. Proteasome inhibitors have been used in the management of patients with multiple myeloma and mantle-cell lymphoma during the last decade. In multiple myeloma, bortezomib, the first-in-class proteasome inhibitor, has shown both in vitro and in vivo regulation of bone remodeling by inhibiting osteoclast function and promoting osteoblast activity. Bortezomib also reduces bone resorption but more importantly increases bone formation and bone mineral density, at least, in subsets of myeloma patients. Thus, bortezomib is recommended for myeloma patients with extended bone disease in combination with bisphosphonates. This review focuses on the effects of the proteasome system on bone metabolism and the implications into the better management of patients with cancer and bone disease.

Figure 1

Pathophysiology of myeloma bone disease and the possible sites of action of bortezomib. Myeloma cells adhere to bone marrow stromal cells (BMSCs) through the binding of very late antigen-4 and lymphocyte function-associated antigen-1 (present on the surface of MM cells) to vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, respectively, which are expressed on stromal cells. The adherence of MM cells to the BMSCs enhances the production of the receptor activator of nuclear factor-kappa B ligand (RANKL) and other cytokines with osteoclast activating function activity (interleukin (IL)-6, IL-11, interleukin-1β, tumor necrosis factors, basic fibroblast growth factor (bFGF), whereas it suppresses the production of OPG (the decoy receptor of RANKL). Furthermore, myeloma cells produce chemokine C-C motif ligand-3, hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF), which enhance the proliferation and differentiation of osteoclast precursors. Myeloma cells may express RANKL, while OPG binds both surface and soluble RANKL, inhibiting osteoclast development and bone resorption. Syndecan 1 (CD138) expressed on the surface of, and secreted from, the myeloma cells can bind soluble OPG, thus preventing its inhibitory effect on RANKL function. Therefore the ratio of RANKL/OPG is increased, leading to osteoclast differentiation, proliferation and activation, and increased bone resorption, as is reflected by the increased levels of bone resorption markers (TRACP-5b, NTX, ICTP, CTX). Bortezomib restores the RANKL/OPG balance and inhibits osteoclast differentiation and activity. The production of VEGF, bFGF and HGF by MM cells and BMSCs results in increased angiogenesis. In turn, IL-6 produced by osteoclasts, endothelial cells and BMSCs increases the growth of MM cells. On the other hand, Wnt signaling inhibitors, such as Dkk-1 and sclerostin, produced by MM cells and osteocytes in apoptosis, respectively, disrupt osteoblast maturation and function, with reduced formation of new bone, reflected by decreased levels of bone formation markers (bALP, OC). The net result of all these complex interactions is tumor expansion and ostelolytic bone disease. Bortezomib inhibits Dkk-1 expression, increases osteoblast differentiation and activity, and leads to increased bone formation.