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Blood, 22 January 2009, Vol. 113, No. 4, pp. 846-855. Prepublished online as a Blood First Edition Paper on October 23, 2008; DOI 10.1182/blood-2008-04-151928. This Article Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: blood-2008-04-151928v1 113/4/846    most recent Alert me when this article is cited Alert me if a correction is posted 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 Okawa, Y. Articles by Anderson, K. C. Search for Related Content PubMed PubMed Citation Articles by Okawa, Y. Articles by Anderson, K. C. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 15, 2008 Accepted August 27, 2008 SNX-2112, a selective Hsp90 inhibitor, potently inhibits tumor cell growth, angiogenesis, and osteoclastogenesis in multiple myeloma and other hematological tumors by abrogating signaling via Akt and ERK Yutaka Okawa*, Teru Hideshima, Paul Steed, Sonia Vallet, Steven Hall, Ken Huang, John Rice, Amy Barabasz, Brianna Foley, Hiroshi Ikeda, Noopur Raje, Tanyel Kiziltepe, Hiroshi Yasui, Sotaro Enatsu, and Kenneth C. Anderson Division of Clinical Oncology and Hematology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States Serenex, Inc., Durham, NC, United States * Corresponding author; email: yutaka_okawa{at}dfci.harvard.edu. Heat-shock protein 90 (Hsp90) acts as a molecular chaperone required for maintaining the conformational stability of client proteins regulating cell proliferation, survival and apoptosis. Here we investigate the biological significance of Hsp90 inhibition in multiple myeloma (MM) and other hematological tumors using an orally available novel small molecule inhibitor SNX-2112 which exhibits unique activities relative to 17-allyamino-17-demethoxy-geldanamycin (17-AAG). SNX-2112 triggers growth inhibition and is more potent than 17-AAG against MM and other malignancies. It induces apoptosis via caspase -8,-9,-3 and PARP cleavage. SNX-2112 inhibits cytokine (IL-6 and IGF-1) -induced Akt and ERK activation and also overcomes the growth advantages conferred by IL-6, IGF-1 and bone marrow stromal cells (BMSCs). Importantly, SNX-2112 inhibits tube formation by HUVEC via abrogation of eNOS/Akt pathway, and markedly inhibits osteoclast formation via downregulation of ERK/c-fos and PU.1. Finally, SNX-2112, delivered by its prodrug SNX-5422, inhibits MM cell growth and prolongs survival in a xenograft murine model. Our results indicate that blockade of Hsp90 by SNX-2112 not only inhibits MM cell growth, but also acts in the BM microenvironment to block angiogenesis and osteoclastogenesis. Taken together, our data provide the framework for clinical studies of SNX-2112 to improve patient outcome in MM and other hematological malignancies. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Mani, D. E. Carrasco, Y. Zhang, K. Takada, M. E. Gatt, J. Dutta-Simmons, H. Ikeda, F. Diaz-Griffero, V. Pena-Cruz, M. Bertagnolli, et al. BCL9 Promotes Tumor Progression by Conferring Enhanced Proliferative, Metastatic, and Angiogenic Properties to Cancer Cells Cancer Res., October 1, 2009; 69(19): 7577 - 7586. [Abstract] [Full Text] [PDF]

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