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Cancer Therapy: Preclinical |
Authors' Affiliations: 1 University of Pittsburgh Cancer Institute, Division of Hematology/Oncology, Department of Internal Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; 2 Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts; and 3 Mayo Clinic College of Medicine, Rochester, Minnesota
Requests for reprints: Irene M. Ghobrial, Dana-Farber Cancer Institute, 44 Binney Street, Mayer 548A, Boston, MA 02115. Phone: 617-632-4198; Fax: 617-632-4862; E-mail: irene_ghobrial{at}dfci.harvard.edu.
Purpose: The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway and the heat shock protein family are up-regulated in multiple myeloma and are both regulators of the cyclin D/retinoblastoma pathway, a critical pathway in multiple myeloma. Inhibitors of mTOR and HSP90 protein have showed in vitro and in vivo single-agent activity in multiple myeloma. Our objective was to determine the effects of the mTOR inhibitor rapamycin and the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) on multiple myeloma cells.
Experimental Design: Multiple myeloma cell lines were incubated with rapamycin (0.1-100 nmol/L) and 17-AAG (100-600 nmol/L) alone and in combination.
Results: In this study, we showed that the combination of rapamycin and 17-AAG synergistically inhibited proliferation, induced apoptosis and cell cycle arrest, induced cleavage of poly(ADP-ribose) polymerase and caspase-8/caspase-9, and dysregulated signaling in the phosphatidylinositol 3-kinase/AKT/mTOR and cyclin D1/retinoblastoma pathways. In addition, we showed that both 17-AAG and rapamycin inhibited angiogenesis and osteoclast formation, indicating that these agents target not only multiple myeloma cells but also the bone marrow microenvironment.
Conclusions: These studies provide the basis for potential clinical evaluation of this combination for multiple myeloma patients.
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