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Blood, 1 February 2006, Vol. 107, No. 3, pp. 1092-1100. Prepublished online as a Blood First Edition Paper on October 18, 2005; DOI 10.1182/blood-2005-03-1158. This Article Full Text (PDF) Supplemental Table and Figures All Versions of this Article: 2005-03-1158v1 107/3/1092    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 Mitsiades, C. S Articles by Anderson, K. C Search for Related Content PubMed PubMed Citation Articles by Mitsiades, C. S Articles by Anderson, K. C Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 23, 2005 Accepted July 27, 2005 Anti-myeloma activity of heat shock protein-90 inhibition Constantine S Mitsiades*, Nicholas S Mitsiades, Ciaran J McMullan, Vassiliki Poulaki, Andrew L Kung, Faith E Davies, Gareth Morgan, Masaharu Akiyama, Reshma Shringarpure, Nikhil C Munshi, Paul G Richardson, Teru Hideshima, Dharminder Chauhan, Xuesong Gu, Charles Bailey, Marie Joseph, Towia A Libermann, Neal S Rosen, and Kenneth C Anderson Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA Departments of Cell Biology and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Royal Marsden Hospital and Institute of Cancer Research, Sutton, Surrey, United Kingdom BIDMC Genomics Center, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, MA, USA Memorial Sloan-Kettering Cancer Center, New York, NY, USA * Corresponding author; email: Constantine_Mitsiades{at}dfci.harvard.edu. We show that multiple myeloma (MM), the 2nd most commonly diagnosed hematologic malignancy, is responsive to hsp90 inhibitors in vitro and in clinically-relevant orthotopic in vivo models, even though this disease does not depend on HER2/neu, bcr/abl, androgen or estrogen receptors or other hsp90 chaperoning clients which are hallmarks of tumor types traditionally viewed as attractive clinical settings for use of hsp90 inhibitors. This class of agents simultaneously suppress in MM cells the expression and/or function multiple levels of insulin-like growth factor receptor (IGF-1R) and interleukin-6 receptor (IL-6R) signaling (e.g. IKK/NF-B, PI-3K/Akt, and Raf/MAPK); and downstream effectors (e.g. proteasome, telomerase and HIF-1 activities). These pleiotropic pro-apoptotic effects allow hsp90 inhibitors to abrogate paracrine, bone marrow stromal cell-derived, protection on MM tumor cells, and sensitize them to other anti-cancer agents, including cytotoxic chemotherapy and proteasome inhibitors. These results indicate that hsp90 can be targeted therapeutically in neoplasias that may not express or depend on molecules previously considered to be the main hsp90 client proteins. This not only suggests a more general role for hsp90 in chaperoning tumor- or tissue type-specific constellations of client proteins with critical involvement in proliferative and anti-apoptotic cellular responses and paves the way for more extensive future therapeutic applications of hsp90 inhibition in diverse neoplasias, including MM. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Ditching the chaperone! Asher Chanan-Khan Blood 2006 107: 850. 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A Pivotal Role for Heat Shock Protein 90 in Ewing Sarcoma Resistance to Anti-Insulin-like Growth Factor 1 Receptor Treatment: In vitro and In vivo Study Cancer Res., August 1, 2008; 68(15): 6260 - 6270. [Abstract] [Full Text] [PDF] M. Zajac, M. V. Moneo, A. Carnero, J. Benitez, and B. Martinez-Delgado Mitotic catastrophe cell death induced by heat shock protein 90 inhibitor in BRCA1-deficient breast cancer cell lines Mol. Cancer Ther., August 1, 2008; 7(8): 2358 - 2366. [Abstract] [Full Text] [PDF] F. Forafonov, O. A. Toogun, I. Grad, E. Suslova, B. C. Freeman, and D. Picard p23/Sba1p Protects against Hsp90 Inhibitors Independently of Its Intrinsic Chaperone Activity Mol. Cell. Biol., May 15, 2008; 28(10): 3446 - 3456. [Abstract] [Full Text] [PDF] M. Chatterjee, C. Rancso, T. Stuhmer, N. Eckstein, M. Andrulis, C. Gerecke, H. Lorentz, H.-D. Royer, and R. C. 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Davies Heat shock protein inhibition is associated with activation of the unfolded protein response pathway in myeloma plasma cells Blood, October 1, 2007; 110(7): 2641 - 2649. [Abstract] [Full Text] [PDF] V. Poulaki, E. Iliaki, N. Mitsiades, C. S. Mitsiades, Y. N. Paulus, D. V. Bula, E. S. Gragoudas, and J. W. Miller Inhibition of Hsp90 attenuates inflammation in endotoxin-induced uveitis FASEB J, July 1, 2007; 21(9): 2113 - 2123. [Abstract] [Full Text] [PDF] H. Younes, X. Leleu, E. Hatjiharissi, A.-S. Moreau, T. Hideshima, P. Richardson, K. C. Anderson, and I. M. Ghobrial Targeting the Phosphatidylinositol 3-Kinase Pathway in Multiple Myeloma Clin. Cancer Res., July 1, 2007; 13(13): 3771 - 3775. [Abstract] [Full Text] [PDF] J. Bae, C. Mitsiades, Y.-T. Tai, R. Bertheau, M. Shammas, R. B. Batchu, C. Li, L. Catley, R. Prabhala, K. C. Anderson, et al. Phenotypic and Functional Effects of Heat Shock Protein 90 Inhibition on Dendritic Cell J. Immunol., June 15, 2007; 178(12): 7730 - 7737. [Abstract] [Full Text] [PDF] R. Spisek, A. Charalambous, A. Mazumder, D. H. Vesole, S. Jagannath, and M. V. Dhodapkar Bortezomib enhances dendritic cell (DC) mediated induction of immunity to human myeloma via exposure of cell surface heat shock protein 90 on dying tumor cells: therapeutic implications Blood, June 1, 2007; 109(11): 4839 - 4845. [Abstract] [Full Text] [PDF] E. Hatjiharissi, H. Ngo, A. A. Leontovich, X. Leleu, M. Timm, M. Melhem, D. George, G. Lu, J. Ghobrial, Y. Alsayed, et al. Proteomic Analysis of Waldenstrom Macroglobulinemia Cancer Res., April 15, 2007; 67(8): 3777 - 3784. [Abstract] [Full Text] [PDF] Y. Alsayed, H. Ngo, J. Runnels, X. Leleu, U. K. Singha, C. M. Pitsillides, J. A. Spencer, T. Kimlinger, J. M. Ghobrial, X. Jia, et al. Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma Blood, April 1, 2007; 109(7): 2708 - 2717. [Abstract] [Full Text] [PDF] J. Sharkey, T. Khong, and A. 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