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Journal of Oncology
Volume 2011 (2011), Article ID 232037, 11 pages
http://dx.doi.org/10.1155/2011/232037
Research Article

Antimyeloma Effects of the Heat Shock Protein 70 Molecular Chaperone Inhibitor MAL3-101

1Division of Hematology/Oncology, Department of Medicine, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA
2Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA
3Department of Biology, Clarion University, Clarion, PA 16214, USA
4Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA
5Department of Chemistry and Center for Chemical Methodologies and Library Development, University of Pittsburgh, Pittsburgh, PA 15260, USA

Received 21 May 2011; Accepted 18 July 2011

Academic Editor: Edward A. Copelan

Copyright © 2011 Marc J. Braunstein et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Multiple myeloma (MM) is the second most common hematologic malignancy and remains incurable, primarily due to the treatment-refractory/resistant nature of the disease. A rational approach to this compelling challenge is to develop new drugs that act synergistically with existing effective agents. This approach will reduce drug concentrations, avoid treatment resistance, and also improve treatment effectiveness by targeting new and nonredundant pathways in MM. Toward this goal, we examined the antimyeloma effects of MAL3-101, a member of a new class of non-ATP-site inhibitors of the heat shock protein (Hsp) 70 molecular chaperone. We discovered that MAL3-101 exhibited antimyeloma effects on MM cell lines in vitro and in vivo in a xenograft plasmacytoma model, as well as on primary tumor cells and bone marrow endothelial cells from myeloma patients. In combination with a proteasome inhibitor, MAL3-101 significantly potentiated the in vitro and in vivo antimyeloma effects. These data support a preclinical rationale for small molecule inhibition of Hsp70 function, either alone or in combination with other agents, as an effective therapeutic strategy for MM.