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Prepublished online as a Blood First Edition Paper on September 26, 2002; DOI 10.1182/blood-2002-08-2543. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-08-2543v1 101/4/1530    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 Hideshima, T. Articles by Anderson, K. C. Search for Related Content PubMed PubMed Citation Articles by Hideshima, T. Articles by Anderson, K. C. Related Collections Cell Adhesion and Motility Oncogenes and Tumor Suppressors Signal Transduction Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 February 2003, Vol. 101, No. 4, pp. 1530-1534 NEOPLASIA Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341 Teru Hideshima, Constantine Mitsiades, Masaharu Akiyama, Toshiaki Hayashi, Dharminder Chauhan, Paul Richardson, Robert Schlossman, Klaus Podar, Nikhil C. Munshi, Nicholas Mitsiades, and Kenneth C. Anderson From the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA. We have recently shown that proteasome inhibitor PS-341 induces apoptosis in drug-resistant multiple myeloma (MM) cells, inhibits binding of MM cells in the bone marrow microenvironment, and inhibits cytokines mediating MM cell growth, survival, drug resistance, and migration in vitro. PS-341 also inhibits human MM cell growth and prolongs survival in a SCID mouse model. Importantly, PS-341 has achieved remarkable clinical responses in patients with refractory relapsed MM. We here demonstrate molecular mechanisms whereby PS-341 mediates anti-MM activity by inducing p53 and MDM2 protein expression; inducing the phosphorylation (Ser15) of p53 protein; activating c-Jun NH2-terminal kinase (JNK), caspase-8, and caspase-3; and cleaving the DNA protein kinase catalytic subunit, ATM, and MDM2. Inhibition of JNK activity abrogates PS-341-induced MM cell death. These studies identify molecular targets of PS-341 and provide the rationale for the development of second-generation, more targeted therapies. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. A. Poff, C. T. Allen, B. Traughber, A. Colunga, J. Xie, Z. Chen, B. J. Wood, C. Van Waes, K. 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