Aplidin (plitidepsin) is a novel anti-myeloma agent with potent anti-resorptive activity mediated by direct effects on osteoclasts
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Jesus Delgado-Calle1,2,4, Noriyoshi Kurihara1, Emily G. Atkinson2, Jessica Nelson1, Kazuaki Miyagawa1, Carlos Maria Galmarini5, G. David Roodman1,4,6 and Teresita Bellido2,3,4,6
1 Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN, USA
2 Department of Anatomy and Cell Biology, Indiana University Sc hool of Medicine, Indianapolis, IN, USA
3 Department of Medicine, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, USA
4 Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA
5 Research Department, PharmaMar S.A., Madrid, Spain
6 Roudebush VA Medical Center, Indianapolis, IN, USA
Keywords: myeloma; osteoclasts; osteocytes; osteoblasts; tumor
Received: November 26, 2018 Accepted: March 23, 2019 Published: April 12, 2019
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.
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