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Blood, 1 June 2005, Vol. 105, No. 11, pp. 4470-4476. Prepublished online as a Blood First Edition Paper on February 10, 2005; DOI 10.1182/blood-2004-09-3794. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-09-3794v1 105/11/4470    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 Hamasaki, M. Articles by Anderson, K. C. Search for Related Content PubMed PubMed Citation Articles by Hamasaki, M. Articles by Anderson, K. C. Related Collections Hematopoiesis and Stem Cells Neoplasia Apoptosis Cell Adhesion and Motility Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Azaspirane (N-N-diethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine) inhibits human multiple myeloma cell growth in the bone marrow milieu in vitro and in vivo Makoto Hamasaki, Teru Hideshima, Pierfrancesco Tassone, Paola Neri, Kenji Ishitsuka, Hiroshi Yasui, Norihiko Shiraishi, Noopur Raje, Shaji Kumar, Donald H. Picker, Gary S. Jacob, Paul G. Richardson, Nikhil C. Munshi, and Kenneth C. Anderson From the Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; and Callisto Pharmaceuticals Inc, New York, NY. Azaspirane (N-N-diethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine; trade name, Atiprimod) is an orally bioavailable cationic amphiphilic compound that significantly inhibits production of interleukin 6 (IL-6) and inflammation in rat arthritis and autoimmune animal models. We here characterize the effect of atiprimod on human multiple myeloma (MM) cells. Azaspirane significantly inhibited growth and induced caspase-mediated apoptosis in drug-sensitive and drug-resistant MM cell lines, as well as patient MM cells. IL-6, insulin-like growth factor 1 (IGF-1), or adherence of MM cells to bone marrow stromal cells (BMSCs) did not protect against atiprimod-induced apoptosis. Both conventional (dexamethasone, doxorubicin, melphalan) and novel (arsenic trioxide) agents augment apoptosis induced by atiprimod. Azaspirane inhibits signal transducer activator of transcription 3 (STAT3) and a PI3-K (phosphatidylinositol 3-kinase) target (Akt), but not extracellular signal-regulated kinase 1 and 2 (ERK1/2), inhibits phosphorylation triggered by IL-6, and also inhibits inhibitorB (IB) and nuclear factor B (NFB) p65 phosphorylation triggered by tumor necrosis factor (TNF-). Of importance, azaspirane inhibits both IL-6 and vascular endothelial growth factor (VEGF) secretion in BMSCs triggered by MM cell binding and also inhibits angiogenesis on human umbilical vein cells (HUVECs). Finally, azaspirane demonstrates in vivo antitumor activity against human MM cell growth in severe combined immunodeficient (SCID) mice. These results, therefore, show that azaspirane both induces MM cell apoptosis and inhibits cytokine secretion in the BM milieu, providing the framework for clinical trials to improve patient outcome in MM. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Wang, L. Zhang, X. Han, J. Yang, J. Qian, S. Hong, P. Lin, Y. Shi, J. Romaguera, L. W. Kwak, et al. A Severe Combined Immunodeficient-hu In vivo Mouse Model of Human Primary Mantle Cell Lymphoma Clin. Cancer Res., April 1, 2008; 14(7): 2154 - 2160. [Abstract] [Full Text] [PDF] M. Wang, L. Zhang, X. Han, J. Yang, J. Qian, S. Hong, F. Samaniego, J. Romaguera, and Q. Yi Atiprimod inhibits the growth of mantle cell lymphoma in vitro and in vivo and induces apoptosis via activating the mitochondrial pathways Blood, June 15, 2007; 109(12): 5455 - 5462. [Abstract] [Full Text] [PDF] S. R. Choudhari, M. A. Khan, G. Harris, D. Picker, G. S. Jacob, T. Block, and K. Shailubhai Deactivation of Akt and STAT3 signaling promotes apoptosis, inhibits proliferation, and enhances the sensitivity of hepatocellular carcinoma cells to an anticancer agent, Atiprimod Mol. Cancer Ther., January 1, 2007; 6(1): 112 - 121. [Abstract] [Full Text] [PDF] W. Dalton and K. C. Anderson Synopsis of a Roundtable on Validating Novel Therapeutics for Multiple Myeloma. Clin. Cancer Res., November 15, 2006; 12(22): 6603 - 6610. [Abstract] [Full Text] [PDF] T. Hideshima, D. Chauhan, P. Richardson, and K. C. Anderson Identification and Validation of Novel Therapeutic Targets for Multiple Myeloma J. Clin. Oncol., September 10, 2005; 23(26): 6345 - 6350. [Abstract] [Full Text] [PDF] P. Tassone, P. Neri, D. R. Carrasco, R. Burger, V. S. Goldmacher, R. Fram, V. Munshi, M. A. Shammas, L. Catley, G. S. Jacob, et al. A clinically relevant SCID-hu in vivo model of human multiple myeloma Blood, July 15, 2005; 106(2): 713 - 716. [Abstract] [Full Text] [PDF]

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