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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 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 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 Okawa, Y. Articles by Anderson, K. C. Search for Related Content PubMed PubMed Citation Articles by Okawa, Y. Articles by Anderson, K. C. Related Collections Lymphoid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA SNX-2112, a selective Hsp90 inhibitor, potently inhibits tumor cell growth, angiogenesis, and osteoclastogenesis in multiple myeloma and other hematologic tumors by abrogating signaling via Akt and ERK Yutaka Okawa1,2, Teru Hideshima1, Paul Steed3, Sonia Vallet1, Steven Hall3, Ken Huang3, John Rice3, Amy Barabasz3, Brianna Foley3, Hiroshi Ikeda1, Noopur Raje1, Tanyel Kiziltepe1, Hiroshi Yasui1, Sotaro Enatsu1, and Kenneth C. Anderson1 1 LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; 2 Division of Clinical Oncology and Hematology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan; and 3 Serenex, Durham, NC 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 biologic significance of Hsp90 inhibition in multiple myeloma (MM) and other hematologic 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 poly (ADP-ribose) polymerase cleavage. SNX-2112 inhibits cytokine-induced Akt and extracellular signal-related kinase (ERK) activation and also overcomes the growth advantages conferred by interleukin-6, insulin-like growth factor-1, and bone marrow stromal cells. Importantly, SNX-2112 inhibits tube formation by human umbilical vein endothelial cells via abrogation of eNOS/Akt pathway and markedly inhibits osteoclast formation via down-regulation 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 bone marrow 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 hematologic 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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