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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 (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 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 Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 7, 2004 Accepted January 18, 2005 In vitro and in vivo activity of atiprimod (N-N-diethl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine) inhibits human multiple myeloma cell growth in the bone marrow milieu 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* Department of Medical Oncology, Dana-Farber Cancer Institute, Jerome Lipper Multiple Myeloma Center, Boston, MA, USA Callisto Pharmaceuticals Inc., New York, NY, USA * Corresponding author; email: kenneth_anderson{at}dfci.harvard.edu. Atiprimod (N-N-diethl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine) is an orally-bioavailable cationic amphiphilic compound which significantly inhibits production of interleukin (IL)-6 and inflammation in rat arthritis and autoimmune animal models. We here characterize the effect of Atiprimod on human multiple myeloma (MM) cells. Atiprimod significantly inhibited growth and induced caspase mediated apoptosis in drug-sensitive and drug-resistant MM cell lines, as well as patient MM cells. Neither IL-6, insulin-like growth factor (IGF)-1 nor adherence of MM cells to bone marrow stromal cells (BMSCs) protects against Atiprimod-induced apoptosis. Both conventional (dexamethasone, doxorubicin, melphalan) and novel (arsenic trioxide) agents augment apoptosis induced by Atiprimod. Atiprimod inhibits STAT3 and Akt, but not ERK1/2, phosphorylation triggered by IL-6; and also inhibits IB and NFB p65 phosphorylation triggered by tumor necrosis factor (TNF)-. Importantly, Atiprimod 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 (HUVEC). Finally, Atiprimod demonstrates in vivo antitumor activity against human MM cell growth in SCID mice. These results therefore show that Atiprimod 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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