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Prepublished online as a Blood First Edition Paper on August 21, 2003; DOI 10.1182/blood-2003-01-0233. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-01-0233v1 2003-01-0233v2 102/7/2615    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 Catley, L. Articles by Anderson, K. C. Search for Related Content PubMed PubMed Citation Articles by Catley, L. Articles by Anderson, K. C. Related Collections Neoplasia Apoptosis Cell Cycle Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 October 2003, Vol. 102, No. 7, pp. 2615-2622 NEOPLASIA NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma Laurence Catley, Ellen Weisberg, Yu-Tzu Tai, Peter Atadja, Stacy Remiszewski, Teru Hideshima, Nicholas Mitsiades, Reshma Shringarpure, Richard LeBlanc, Dharminder Chauhan, Nikhil C. Munshi, Robert Schlossman, Paul Richardson, James Griffin, and Kenneth C. Anderson From the Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; the Department of Medicine, Harvard Medical School, Boston, MA; and Novartis Institutes for Biomedical Research, Oncology Research, East Hanover, NJ. Histone deacetylase (HDAC) inhibitors are emerging as a promising new treatment strategy in hematologic malignancies. Here we show that NVP-LAQ824, a novel hydroxamic acid derivative, induces apoptosis at physiologically achievable concentrations (median inhibitory concentration [IC50] of 100 nM at 24 hours) in multiple myeloma (MM) cell lines resistant to conventional therapies. MM.1S myeloma cell proliferation was also inhibited when cocultured with bone marrow stromal cells, demonstrating ability to overcome the stimulatory effects of the bone marrow microenvironment. Importantly, NVP-LAQ824 also inhibited patient MM cell growth in a dose- and time-dependent manner. NVP-LAQ824-induced apoptotic signaling includes up-regulation of p21, caspase cascade activation, and poly (adenosine diphosphate [ADP]) ribose (PARP) cleavage. Apoptosis was confirmed with cell cycle analysis and annexin-propidium iodide staining. Interestingly, treatment of MM cells with NVPLAQ824 also led to proteasome inhibition, as determined by reduced proteasome chymotrypsin-like activity and increased levels of cellular polyubiquitin conjugates. Finally, a study using NVP-LAQ824 in a preclinical murine myeloma model provides in vivo relevance to our in vitro studies. Taken together, these findings provide the framework for NVP-LAQ824 as a novel therapeutic in MM. (Blood. 2003;102:2615-2622) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. D. Vo, R. M. Prins, J. L. Begley, T. R. Donahue, L. F. Morris, K. W. Bruhn, P. de la Rocha, M.-Y. Yang, S. Mok, H. J. Garban, et al. Enhanced Antitumor Activity Induced by Adoptive T-Cell Transfer and Adjunctive Use of the Histone Deacetylase Inhibitor LAQ824 Cancer Res., November 15, 2009; 69(22): 8693 - 8699. [Abstract] [Full Text] [PDF] A. Badros, A. M. Burger, S. Philip, R. Niesvizky, S. S. 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