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Blood, 1 March 2008, Vol. 111, No. 5, pp. 2765-2775. Prepublished online as a Blood First Edition Paper on December 5, 2007; DOI 10.1182/blood-2007-07-100651. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-07-100651v1 111/5/2765    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 Piva, R. Articles by Inghirami, G. PubMed PubMed Citation Articles by Piva, R. Articles by Inghirami, G. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA CEP-18770: A novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib Roberto Piva1,3, Bruce Ruggeri4, Michael Williams4, Giulia Costa1, Ilaria Tamagno1, Dario Ferrero5, Valentina Giai5, Marta Coscia1,5, Silvia Peola1,5, Massimo Massaia1,5, Gabriella Pezzoni6, Cecilia Allievi6, Nicoletta Pescalli6, Mara Cassin6, Stefano di Giovine6, Paola Nicoli6, Paola de Feudis6, Ivan Strepponi6, Ilaria Roato6, Riccardo Ferracini7, Benedetta Bussolati1,8, Giovanni Camussi1,8, Susan Jones-Bolin4, Kathryn Hunter4, Hugh Zhao4, Antonino Neri9, Antonio Palumbo5, Celia Berkers10, Huib Ovaa10, Alberto Bernareggi11, and Giorgio Inghirami1,3 1 Center for Experimental Research and Medical Studies (CeRMS) and 2 Department of Biomedical Sciences and Human Oncology, University of Torino, Torino, Italy; 3 Department of Pathology and New York University Cancer Center, New York University School of Medicine, New York; 4 Discovery Research, Cephalon, West Chester, PA; 5 Hematology Division, University of Torino, Torino, Italy; 6 Sede Secondaria Della Cell Therapeutics, Bresso, Italy; 7 Orthopedic and Traumatology, San Giovanni Battista of Torino, Torino, Italy; 8 Department of Internal Medicine, University of Torino, Torino, Italy; 9 Laboratory of Experimental Hematology and Molecular Genetics, Ospedale Maggiore Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milano, Italy; 10 Netherlands Cancer Institute, Amsterdam, the Netherlands; and 11 RBM, Brescia, Italy Modulating protein ubiquitination via proteasome inhibition represents a promising target for cancer therapy, because of the higher sensitivity of cancer cells to the cytotoxic effects of proteasome inhibition. Here we show that CEP-18770 is a novel orally-active inhibitor of the chymotrypsin-like activity of the proteasome that down-modulates the nuclear factor-B (NF-B) activity and the expression of several NF-B downstream effectors. CEP-18770 induces apoptotic cell death in multiple myeloma (MM) cell lines and in primary purified CD138-positive explant cultures from untreated and bortezomib-treated MM patients. In vitro, CEP-18770 has a strong antiangiogenic activity and potently represses RANKL–induced osteoclastogenesis. Importantly, CEP-18770 exhibits a favorable cytotoxicity profile toward normal human epithelial cells, bone marrow progenitors, and bone marrow–derived stromal cells. Intravenous and oral administration of CEP-18770 resulted in a more sustained pharmacodynamic inhibition of proteasome activity in tumors relative to normal tissues, complete tumor regression of MM xenografts and improved overall median survival in a systemic model of human MM. Collectively, these findings provide evidence for the utility of CEP-18770 as a novel orally active proteasome inhibitor with a favorable tumor selectivity profile for the treatment of MM and other malignancies responsive to proteasome inhibition. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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