Abstract
Despite recent progress in its treatment, Multiple Myeloma (MM) remains incurable and its associated bone disease persists even after complete remission. Thus, identification of new therapeutic agents that simultaneously suppress MM growth and protect bone is an unmet need. Herein, we examined the effects of Aplidin, a novel anti-cancer marine-derived compound, on MM and bone cells. In vitro, Aplidin potently inhibited MM cell growth and induced apoptosis, effects that were enhanced by dexamethasone (Dex) and bortezomib (Btz). Aplidin modestly reduced osteocyte/osteoblast viability and decreased osteoblast mineralization, effects that were enhanced by Dex and partially prevented by Btz. Further, Aplidin markedly decreased osteoclast precursor numbers and differentiation, and reduced mature osteoclast number and resorption activity. Moreover, Aplidin reduced Dex-induced osteoclast differentiation and further decreased osteoclast number when combined with Btz. Lastly, Aplidin alone, or suboptimal doses of Aplidin combined with Dex or Btz, decreased tumor growth and bone resorption in ex vivo bone organ cultures that reproduce the 3D-organization and the cellular diversity of the MM/bone marrow niche. These results demonstrate that Aplidin has potent anti-myeloma and anti-resorptive properties, and enhances proteasome inhibitors blockade of MM growth and bone destruction.
Highlights
Multiple myeloma (MM) is the second most common hematologic malignancy and the most frequent cancer that involves bone [1, 2]
These results demonstrate that Aplidin has potent anti-myeloma and antiresorptive properties, and enhances proteasome inhibitors blockade of MM growth and bone destruction
Using in vitro approaches and an ex vivo 3D model of MM bone disease, we found that Aplidin decreased MM cell viability, and that this action was enhanced by the anti-MM drugs Dex and Bortezomib (Btz)
Summary
Multiple myeloma (MM) is the second most common hematologic malignancy and the most frequent cancer that involves bone [1, 2]. The bone/bone marrow (BM) niche plays a critical role in MM onset and progression. MM cells locate in specialized niches in the BM where they interact with stromal cells, endothelial cells, immune cells, osteoblasts, osteoclasts, adipocytes, and osteocytes [2, 3]. These interactions transform the bone/BM niche into an ideal environment for the proliferation and survival of MM cells. Actively expanding MM cells increase osteoclast numbers and activity, leading to development of lytic bone lesions that rarely heal due to a concomitant suppression of osteoblast bone forming activity [1, 4]. Osteolytic lesions persist in patients in remission with no evidence of marrow infiltration by MM cells [4, 5], prompting a continued search for additional therapeutic options that inhibit MM growth and protect bone health
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