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Blood, 30 April 2009, Vol. 113, No. 18, pp. 4341-4351.
Prepublished online as a Blood First Edition Paper on January 12, 2009; DOI 10.1182/blood-2008-10-186668.
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Submitted October 30, 2008
Accepted December 31, 2008
The CXCR4 inhibitor AMD3100 disrupts the interaction of multiple myeloma cells with the bone marrow microenvironment and enhances their sensitivity to therapy
Abdel Kareem Azab, Judith M. Runnels, Costas Pitsillides, Anne-Sophie Moreau, Feda Azab, Xavier Leleu, Xiaoying Jia, Renee Wright, Beatriz Ospina, Alicia L. Carlson, Clemens Alt, Nicholas Burwick, Aldo M. Roccaro, Hai T. Ngo, Mena Farag, Molly R. Melhem, Antonio Sacco, Nikhil C. Munshi, Teru Hideshima, Barrett J. Rollins, Kenneth C. Anderson, Andrew L. Kung, Charles P. Lin, and Irene M. Ghobrial*
Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States
Advanced Microscopy Program, Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, United States
Pediatric Oncology, Dana-Farber Cancer Institute, Children's Hospital Boston and Harvard Medical School, Boston, MA, United States
* Corresponding author; email: irene_ghobrial{at}dfci.harvard.edu.
The interaction of multiple myeloma (MM) cells with their microenvironment in the bone marrow (BM) provides a protective environment and resistance to therapeutic agents. We hypothesized that disruption of the interaction of MM cells with their BM milieu would lead to their sensitization to therapeutic agents such as bortezomib, melphalan, doxorubicin, and dexamethasone. We report that the CXCR4 inhibitor AMD3100 induces disruption of the interaction of MM cells with the BM reflected by mobilization of MM cells into the circulation in-vivo, with kinetics that differed from that of hematopoeitic stem cells. AMD3100 enhanced sensitivity of MM cell to multiple therapeutic agents in vitro by disrupting adhesion of MM cells to bone marrow stromal cells (BMSCs). Moreover, AMD3100 increased mobilization of MM cell to the circulation in vivo, increased the ratio of apoptotic circulating MM cells, and enhanced the tumor reduction induced by bortezomib. Mechanistically, AMD3100 significantly inhibited Akt phosphorylation and enhanced PARP cleavage due to bortezomib, in the presence of BMSCs in co-culture. These experiments provide a proof of concept for the use of agents that disrupt interaction with the microenvironment for enhancement of efficacy of cytotoxic agents in cancer therapy.
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