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Blood, 15 October 2009, Vol. 114, No. 16, pp. 3439-3447. Prepublished online as a Blood First Edition Paper on August 11, 2009; DOI 10.1182/blood-2009-05-223677. This Article Full Text Full Text (PDF) Supplemental Methods and Table All Versions of this Article: blood-2009-05-223677v1 114/16/3439    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 CrossRef Google Scholar Articles by Parlati, F. Articles by Bennett, M. K. PubMed PubMed Citation Articles by Parlati, F. Articles by Bennett, M. K. Related Collections Myeloid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  MYELOID NEOPLASIA Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome Francesco Parlati1, Susan J. Lee1, Monette Aujay1, Erika Suzuki1, Konstantin Levitsky1, James B. Lorens2, David R. Micklem2, Paulina Ruurs2, Catherine Sylvain1, Yan Lu1, Kevin D. Shenk1, and Mark K. Bennett1 1 Department of Research, Proteolix Inc, South San Francisco, CA; and 2 Department of Biomedicine, University of Bergen, Bergen, Norway Carfilzomib is a proteasome inhibitor in clinical development that primarily targets the chymotrypsin-like (CT-L) subunits in both the constitutive proteasome (c20S) and the immunoproteasome (i20S). To investigate the impact of inhibiting the CT-L activity with carfilzomib, we set out to quantitate the levels of CT-L subunits β5 from the c20S and LMP7 from the i20S in normal and malignant hematopoietic cells. We found that the i20S is a major form of the proteasome expressed in cells of hematopoietic origin, including multiple myeloma (MM) CD138+ tumor cells. Although specific inhibition of either LMP7 or β5 alone was insufficient to produce an antitumor response, inhibition of all proteasome subunits was cytotoxic to both hematologic tumor cells and peripheral blood mononuclear cells. However, selective inhibition of both β5 and LMP7 was sufficient to induce an antitumor effect in MM, non-Hodgkin lymphoma, and leukemia cells while minimizing the toxicity toward nontransformed cells. In MM tumor cells, CT-L inhibition alone was sufficient to induce proapoptotic sequelae, including proteasome substrate accumulation, Noxa and caspase 3/7 induction, and phospho-eIF2 suppression. These data support a hypothesis that hematologic tumor cells are uniquely sensitive to CT-L inhibition and provide a mechanistic understanding of the clinical safety profile and antitumor activity of proteasome inhibitors. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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