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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 (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 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 Social Bookmarking                   What's this? Submitted August 21, 2002 Accepted September 17, 2002 Molecular mechanisms mediating anti-myeloma 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* Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA, USA * Corresponding author; email: kenneth_anderson{at}dfci.harvard.edu. 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 include: induction of p53 and MDM2 proteins; phosphorylationSer15 of p53; activation of c-Jun NH2-terminal kinase (JNK), caspases-8 and -3; as well as cleavage 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 development of next generation more targeted therapies. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. G. Ooi, P. J. Hayden, V. Kotoula, D. W. McMillin, E. Charalambous, E. Daskalaki, N. S. Raje, N. C. Munshi, D. Chauhan, T. Hideshima, et al. Interactions of the Hdm2/p53 and Proteasome Pathways May Enhance the Antitumor Activity of Bortezomib Clin. Cancer Res., December 1, 2009; 15(23): 7153 - 7160. 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Oncol., January 20, 2005; 23(3): 630 - 639. [Abstract] [Full Text] [PDF] R. Z. Orlowski The Ubiquitin Proteasome Pathway from Bench to Bedside Hematology, January 1, 2005; 2005(1): 220 - 225. [Abstract] [Full Text] [PDF] G. W. Small, Y. Y. Shi, N. A. Edmund, S. Somasundaram, D. T. Moore, and R. Z. Orlowski Evidence That Mitogen-Activated Protein Kinase Phosphatase-1 Induction by Proteasome Inhibitors Plays an Antiapoptotic Role Mol. Pharmacol., December 1, 2004; 66(6): 1478 - 1490. [Abstract] [Full Text] [PDF] A. Fribley, Q. Zeng, and C.-Y. Wang Proteasome Inhibitor PS-341 Induces Apoptosis through Induction of Endoplasmic Reticulum Stress-Reactive Oxygen Species in Head and Neck Squamous Cell Carcinoma Cells Mol. Cell. Biol., November 15, 2004; 24(22): 9695 - 9704. [Abstract] [Full Text] [PDF] R. A. Kyle and S. V. Rajkumar Multiple Myeloma N. Engl. J. Med., October 28, 2004; 351(18): 1860 - 1873. [Full Text] [PDF] D. Chauhan, G. Li, K. Podar, T. Hideshima, C. Mitsiades, R. Schlossman, N. Munshi, P. Richardson, F. E. Cotter, and K. C. Anderson Targeting mitochondria to overcome conventional and bortezomib/proteasome inhibitor PS-341 resistance in multiple myeloma (MM) cells Blood, October 15, 2004; 104(8): 2458 - 2466. [Abstract] [Full Text] [PDF] Q. Xu, M. Farah, J. M. Webster, and R. J.H. Wojcikiewicz Bortezomib rapidly suppresses ubiquitin thiolesterification to ubiquitin-conjugating enzymes and inhibits ubiquitination of histones and type I inositol 1,4,5-trisphosphate receptor Mol. Cancer Ther., October 1, 2004; 3(10): 1263 - 1269. [Abstract] [Full Text] [PDF] T. Hideshima, P. L. Bergsagel, W. M. Kuehl, and K. C. Anderson Advances in biology of multiple myeloma: clinical applications Blood, August 1, 2004; 104(3): 607 - 618. [Abstract] [Full Text] [PDF] J. An, Y. Sun, M. Fisher, and M. B. Rettig Maximal apoptosis of renal cell carcinoma by the proteasome inhibitor bortezomib is nuclear factor-{kappa}B dependent Mol. Cancer Ther., June 1, 2004; 3(6): 727 - 736. [Abstract] [Full Text] [PDF] X.-Y. Pei, Y. Dai, and S. Grant Synergistic Induction of Oxidative Injury and Apoptosis in Human Multiple Myeloma Cells by the Proteasome Inhibitor Bortezomib and Histone Deacetylase Inhibitors Clin. Cancer Res., June 1, 2004; 10(11): 3839 - 3852. [Abstract] [Full Text] [PDF] P. Bonvini, H. D. Rosa, N. Vignes, and A. Rosolen Ubiquitination and Proteasomal Degradation of Nucleophosmin-Anaplastic Lymphoma Kinase Induced by 17-Allylamino-Demethoxygeldanamycin: Role of the Co-Chaperone Carboxyl Heat Shock Protein 70-Interacting Protein Cancer Res., May 1, 2004; 64(9): 3256 - 3264. [Abstract] [Full Text] [PDF] Y. Dai, X.-Y. Pei, M. Rahmani, D. H. Conrad, P. Dent, and S. Grant Interruption of the NF-{kappa}B pathway by Bay 11-7082 promotes UCN-01-mediated mitochondrial dysfunction and apoptosis in human multiple myeloma cells Blood, April 1, 2004; 103(7): 2761 - 2770. [Abstract] [Full Text] [PDF] K. C. Anderson Proteasome inhibitor therapy of multiple myeloma. AACR Meeting Abstracts, March 1, 2004; 2004(1): 1316 - 1316. [Abstract] T. Hideshima, D. Chauhan, T. Hayashi, K. Podar, M. Akiyama, C. Mitsiades, N. MItsiades, B. Gong, L. Bonham, P. de Vries, et al. Antitumor Activity of Lysophosphatidic Acid Acyltransferase-{beta} Inhibitors, a Novel Class of Agents, in Multiple Myeloma Cancer Res., December 1, 2003; 63(23): 8428 - 8436. [Abstract] [Full Text] [PDF] S. A. Williams and D. J. McConkey The Proteasome Inhibitor Bortezomib Stabilizes a Novel Active Form of p53 in Human LNCaP-Pro5 Prostate Cancer Cells Cancer Res., November 1, 2003; 63(21): 7338 - 7344. [Abstract] [Full Text] [PDF] A.-H. Lee, N. N. Iwakoshi, K. C. Anderson, and L. H. Glimcher Inaugural Article: Proteasome inhibitors disrupt the unfolded protein response in myeloma cells PNAS, August 19, 2003; 100(17): 9946 - 9951. [Abstract] [Full Text] [PDF] P. G. Richardson, B. Barlogie, J. Berenson, S. Singhal, S. Jagannath, D. Irwin, S. V. Rajkumar, G. Srkalovic, M. Alsina, R. Alexanian, et al. A Phase 2 Study of Bortezomib in Relapsed, Refractory Myeloma N. Engl. J. Med., June 26, 2003; 348(26): 2609 - 2617. [Abstract] [Full Text] [PDF] J. Shaughnessy, J. Jacobson, J. Sawyer, J. McCoy, A. Fassas, F. Zhan, K. Bumm, J. Epstein, E. Anaissie, S. Jagannath, et al. Continuous absence of metaphase-defined cytogenetic abnormalities, especially of chromosome 13 and hypodiploidy, ensures long-term survival in multiple myeloma treated with Total Therapy I: interpretation in the context of global gene expression Blood, May 15, 2003; 101(10): 3849 - 3856. [Abstract] [Full Text] [PDF] N. Mitsiades, C. S. Mitsiades, P. G. Richardson, V. Poulaki, Y.-T. Tai, D. Chauhan, G. Fanourakis, X. Gu, C. Bailey, M. Joseph, et al. The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications Blood, March 15, 2003; 101(6): 2377 - 2380. 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