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Blood, 15 February 2008, Vol. 111, No. 4, pp. 2220-2229. Prepublished online as a Blood First Edition Paper on November 26, 2007; DOI 10.1182/blood-2007-07-102632. This Article Full Text (PDF) All Versions of this Article: blood-2007-07-102632v1 111/4/2220    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 Nefedova, Y. Articles by Gabrilovich, D. I. Search for Related Content PubMed PubMed Citation Articles by Nefedova, Y. Articles by Gabrilovich, D. I. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 23, 2007 Accepted November 11, 2007 Inhibition of Notch signaling induces apoptosis of myeloma cells and enhances sensitivity to chemotherapy Yulia Nefedova*, Daniel M Sullivan, Sophie C Bolick, William S Dalton, and Dmitry I. Gabrilovich H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL, United States * Corresponding author; email: julia.nefedova{at}moffitt.org. Drug resistance remains a critical problem in the treatment of multiple myeloma patients. Recent studies have determined that Notch signaling plays a major role in bone marrow (BM) stroma mediated protection of myeloma cells from de novo drug-induced apoptosis. Here, we investigated whether pharmacological inhibition of Notch signaling could affect the viability of myeloma cells and their sensitivity to chemotherapy. Treatment with a -secretase inhibitor (GSI) alone induced apoptosis of myeloma cells via specific inhibition of Notch signaling. At concentrations toxic for myeloma cell lines and primary myeloma cells, GSI did not affect normal BM or peripheral blood mononuclear cells. Treatment with GSI prevented BM stroma mediated protection of myeloma cells from drug-induced apoptosis. The cytotoxic effect of GSI was mediated via Hes-1 and up-regulation of the pro-apoptotic protein Noxa. In vivo experiments using xenograft and SCID-hu models of multiple myeloma demonstrated substantial antitumor effect of GSI. In addition, GSI significantly improved the cytotoxicity of the chemotherapeutic drugs doxorubicin and melphalan. Thus, this study demonstrates that inhibition of Notch signaling prevents BM mediated drug resistance and sensitizes myeloma cells to chemotherapy. This may represent a promising approach for therapeutic intervention in multiple myeloma. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Monticone, E. Biollo, A. Fabiano, M. Fabbi, A. Daga, F. Romeo, M. Maffei, A. Melotti, W. Giaretti, G. Corte, et al. z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor-Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response Mol. Cancer Res., November 1, 2009; 7(11): 1822 - 1834. [Abstract] [Full Text] [PDF] O. Meurette, S. Stylianou, R. Rock, G. M. Collu, A. P. Gilmore, and K. Brennan Notch Activation Induces Akt Signaling via an Autocrine Loop to Prevent Apoptosis in Breast Epithelial Cells Cancer Res., June 15, 2009; 69(12): 5015 - 5022. [Abstract] [Full Text] [PDF] Y. Hiruma, T. Honjo, D. F. Jelinek, J. J. Windle, J. Shin, G. D. Roodman, and N. Kurihara Increased signaling through p62 in the marrow microenvironment increases myeloma cell growth and osteoclast formation Blood, May 14, 2009; 113(20): 4894 - 4902. [Abstract] [Full Text] [PDF] T. Quillard, S. Coupel, F. Coulon, J. Fitau, M. Chatelais, M.C. Cuturi, E. Chiffoleau, and B. Charreau Impaired Notch4 Activity Elicits Endothelial Cell Activation and Apoptosis: Implication for Transplant Arteriosclerosis Arterioscler Thromb Vasc Biol, December 1, 2008; 28(12): 2258 - 2265. [Abstract] [Full Text] [PDF] D.-M. Shin, D. J. Shaffer, H. Wang, D. C. Roopenian, and H. C. Morse III NOTCH Is Part of the Transcriptional Network Regulating Cell Growth and Survival in Mouse Plasmacytomas Cancer Res., November 15, 2008; 68(22): 9202 - 9211. [Abstract] [Full Text] [PDF]

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