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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. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2008-10-186668v1 113/18/4341    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Azab, A. K. Articles by Ghobrial, I. M. Search for Related Content PubMed PubMed Citation Articles by Azab, A. K. Articles by Ghobrial, I. M. Related Collections Lymphoid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA CXCR4 inhibitor AMD3100 disrupts the interaction of multiple myeloma cells with the bone marrow microenvironment and enhances their sensitivity to therapy Abdel Kareem Azab1,2,*, Judith M. Runnels1,2,*, Costas Pitsillides2, Anne-Sophie Moreau1, Feda Azab1, Xavier Leleu1, Xiaoying Jia1, Renee Wright3, Beatriz Ospina3, Alicia L. Carlson2, Clemens Alt2, Nicholas Burwick1, Aldo M. Roccaro1, Hai T. Ngo1, Mena Farag1, Molly R. Melhem1, Antonio Sacco1, Nikhil C. Munshi1, Teru Hideshima1, Barrett J. Rollins1, Kenneth C. Anderson1, Andrew L. Kung3, Charles P. Lin2,, and Irene M. Ghobrial1, 1 Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; 2 Advanced Microscopy Program, Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital, Boston; and 3 Pediatric Oncology, Dana-Farber Cancer Institute, Children's Hospital Boston and Harvard Medical School, Boston, MA 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 hematopoietic 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 cells 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 poly(ADP-ribose) polymerase (PARP) cleavage as a result of bortezomib, in the presence of BMSCs in coculture. 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. A. Burger, P. Ghia, A. Rosenwald, and F. Caligaris-Cappio The microenvironment in mature B-cell malignancies: a target for new treatment strategies Blood, October 15, 2009; 114(16): 3367 - 3375. [Abstract] [Full Text] [PDF] M. Heuser, F. Kuchenbauer, B. Argiropoulos, S. Sekulovic, M. Leung, M. Stasiak, A. Ganser, and R. K. Humphries Priming reloaded? Blood, July 23, 2009; 114(4): 925 - 926. [Full Text] [PDF] A. K. Azab and I. M. Ghobrial Response: Sensitization initiated Blood, July 23, 2009; 114(4): 926 - 927. [Full Text] [PDF]

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