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Blood, 15 December 2008, Vol. 112, No. 13, pp. 5095-5102. Prepublished online as a Blood First Edition Paper on September 29, 2008; DOI 10.1182/blood-2007-12-129718. This Article Full Text (PDF) Supplemental Table and Figure All Versions of this Article: blood-2007-12-129718v1 112/13/5095    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 Nelson, E. A Articles by Frank, D. A Search for Related Content PubMed PubMed Citation Articles by Nelson, E. A Articles by Frank, D. A Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 19, 2007 Accepted September 7, 2008 Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3 Erik A Nelson, Sarah R Walker, Alicia Kepich, Laurie B Gashin, Teru Hideshima, Hiroshi Ikeda, Dharminder Chauhan, Kenneth C. Anderson, and David A Frank* Department of Medical Oncology, Dana-Farber Cancer Institute, Departments of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, United States * Corresponding author; email: david_frank{at}dfci.harvard.edu. Constitutive activation of the transcription factor STAT3 contributes to the pathogenesis of many cancers, including multiple myeloma (MM). Since STAT3 is dispensable in most normal tissue, targeted inhibition of STAT3 is an attractive therapy for patients with these cancers. To identify STAT3 inhibitors, we developed a transcriptionally based assay and screened a library of compounds known to be safe in humans. We found the drug nifuroxazide to be an effective inhibitor of STAT3 function. Nifuroxazide inhibits the constitutive phosphorylation of STAT3 in MM cells by reducing Jak kinase autophosphorylation, and leads to downregulation of the STAT3 target gene Mcl-1. Nifuroxazide causes a decrease in viability of primary myeloma cells and myeloma cell lines containing STAT3 activation, but not normal peripheral blood mononuclear cells. Although bone marrow stromal cells provide survival signals to myeloma cells, nifuroxazide can overcome this survival advantage. Reflecting the interaction of STAT3 with other cellular pathways, nifuroxazide shows enhanced cytotoxicity when combined with either the histone deacetylase inhibitor depsipeptide or the MEK inhibitor UO126. Therefore, using a mechanistic-based screen, we identified the clinically relevant drug nifuroxazide as a potent inhibitor of STAT signaling which shows cytotoxicity against myeloma cells that depend on STAT3 for survival. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. R. Walker, E. A. Nelson, L. Zou, M. Chaudhury, S. Signoretti, A. Richardson, and D. A. Frank Reciprocal Effects of STAT5 and STAT3 in Breast Cancer Mol. Cancer Res., June 1, 2009; 7(6): 966 - 976. [Abstract] [Full Text] [PDF] K. M. Sakamoto and D. A. Frank CREB in the Pathophysiology of Cancer: Implications for Targeting Transcription Factors for Cancer Therapy Clin. Cancer Res., April 15, 2009; 15(8): 2583 - 2587. [Abstract] [Full Text] [PDF]

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