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Aplidin, a Marine Organism–Derived Compound with Potent Antimyeloma Activity In vitro and In vivo

¹ Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute; ² Department of Medicine, Harvard Medical School, Boston, Massachusetts; ³ Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, Universidad de Salamanca-CSIC, Salamanca; ⁴ Departamento de Hematología and ⁵ Unidad de investigación, Hospital Universitario de Salamanca, Spain; ⁶ PharmaMar, Madrid, Spain; and ⁷ PharmaMar, Inc., Cambridge, Massachusetts

Requests for reprints: Constantine S. Mitsiades, Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115. Phone: 617-632-1962; Fax: 617-812-7701; E-mail: Constantine_Mitsiades{at}dfci.harvard.edu.

Key Words: Multiple myeloma • Aplidin • drug-sensitivity profiles • bone marrow microenvironment

Despite recent progress in its treatment, multiple myeloma (MM) remains incurable, thus necessitating identification of novel anti-MM agents. We report that the marine-derived cyclodepsipeptide Aplidin exhibits, at clinically achievable concentrations, potent in vitro activity against primary MM tumor cells and a broad spectrum of human MM cell lines, including cells resistant to conventional (e.g., dexamethasone, alkylating agents, and anthracyclines) or novel (e.g., thalidomide and bortezomib) anti-MM agents. Aplidin is active against MM cells in the presence of proliferative/antiapoptotic cytokines or bone marrow stromal cells and has additive or synergistic effects with some of the established anti-MM agents. Mechanistically, a short in vitro exposure to Aplidin induces MM cell death, which involves activation of p38 and c-jun NH₂-terminal kinase signaling, Fas/CD95 translocation to lipid rafts, and caspase activation. The anti-MM effect of Aplidin is associated with suppression of a constellation of proliferative/antiapoptotic genes (e.g., MYC, MYBL2, BUB1, MCM2, MCM4, MCM5, and survivin) and up-regulation of several potential regulators of apoptosis (including c-JUN, TRAIL, CASP9, and Smac). Aplidin exhibited in vivo anti-MM activity in a mouse xenograft model. The profile of the anti-MM activity of Aplidin in our preclinical models provided the framework for its clinical testing in MM, which has already provided favorable preliminary results. [Cancer Res 2008;68(13):5216–25]