SEARCH:   Advanced

Blood, 1 August 2005, Vol. 106, No. 3, pp. 1042-1047. Prepublished online as a Blood First Edition Paper on April 12, 2005; DOI 10.1182/blood-2005-01-0320. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-01-0320v1 106/3/1042    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 Raje, N. Articles by Anderson, K. C. Search for Related Content PubMed PubMed Citation Articles by Raje, N. Articles by Anderson, K. C. Related Collections Neoplasia Cell Cycle Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Seliciclib (CYC202 or R-roscovitine), a small-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulation of Mcl-1 in multiple myeloma Noopur Raje, Shaji Kumar, Teru Hideshima, Aldo Roccaro, Kenji Ishitsuka, Hiroshi Yasui, Norihiko Shiraishi, Dharminder Chauhan, Nikhil C. Munshi, Simon R. Green, and Kenneth C. Anderson From the Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute, VA Boston Healthcare System, and Harvard Medical School, Boston, MA; Division of Hematology, Mayo Clinic, Rochester, MN; and Cyclacel Ltd, Dundee, United Kingdom. Cyclin-dependent kinase (CDK) inhibitors have the potential to induce cell-cycle arrest and apoptosis in cancer cells. Seliciclib (CYC202 or R-roscovitine) is a potent CDK inhibitor currently undergoing phase-2 clinical testing in lung and B-cell malignancies. Here we studied the in vitro cytotoxic activity of seliciclib against multiple myeloma (MM) cells. Our data demonstrate that seliciclib has potent cytotoxicity against MM cells that are both sensitive and resistant to conventional therapy as well as primary MM cells from patients. Cell-cycle and Western blot analysis confirmed apoptosis. Importantly, seliciclib triggered a rapid down-regulation of Mcl-1 transcription and protein expression independent of caspase cleavage. Adherence of MM cells to bone marrow stromal cells (BMSCs) induced increased Mcl-1 expression associated with signal transducer and activator of transcription 3 (STAT3) phosphorylation, which was inhibited in a time- and dose-dependent manner by seliciclib. Furthermore, seliciclib inhibited interleukin 6 (IL-6) transcription and secretion triggered by tumor cell binding to BMSCs. Up-regulation of Mcl-1 expression in cocultures was only partially blocked by neutralizing antibody to IL-6, suggesting alternative mechanisms of Mcl-1 modulation by seliciclib. Finally, combination studies of seliciclib with doxorubicin and bortezomib show in vitro synergism, providing the rationale for testing these drug combinations to improve patient outcome in MM. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Chen, Y. Dai, X.-Y. Pei, and S. Grant Bim Upregulation by Histone Deacetylase Inhibitors Mediates Interactions with the Bcl-2 Antagonist ABT-737: Evidence for Distinct Roles for Bcl-2, Bcl-xL, and Mcl-1 Mol. Cell. Biol., December 1, 2009; 29(23): 6149 - 6169. [Abstract] [Full Text] [PDF] A. B.Y. Hui, S. Yue, W. Shi, N. M. Alajez, E. Ito, S. R. Green, S. Frame, B. O'Sullivan, and F.-F. Liu Therapeutic Efficacy of Seliciclib in Combination with Ionizing Radiation for Human Nasopharyngeal Carcinoma Clin. Cancer Res., June 1, 2009; 15(11): 3716 - 3724. [Abstract] [Full Text] [PDF] X. Garrofe-Ochoa, R. M. Melero-Fernandez de Mera, F. J. Fernandez-Gomez, J. Ribas, J. Jordan, and J. Boix BAX and BAK proteins are required for cyclin-dependent kinase inhibitory drugs to cause apoptosis Mol. Cancer Ther., December 1, 2008; 7(12): 3800 - 3806. [Abstract] [Full Text] [PDF] V. Del Gaizo Moore, K. D. Schlis, S. E. Sallan, S. A. Armstrong, and A. Letai BCL-2 dependence and ABT-737 sensitivity in acute lymphoblastic leukemia Blood, February 15, 2008; 111(4): 2300 - 2309. [Abstract] [Full Text] [PDF] E. F. Lee, P. E. Czabotar, M. F. van Delft, E. M. Michalak, M. J. Boyle, S. N. Willis, H. Puthalakath, P. Bouillet, P. M. Colman, D. C.S. Huang, et al. A novel BH3 ligand that selectively targets Mcl-1 reveals that apoptosis can proceed without Mcl-1 degradation J. Cell Biol., January 28, 2008; 180(2): 341 - 355. [Abstract] [Full Text] [PDF] C. M. Stellrecht, C. J. Phillip, F. Cervantes-Gomez, and V. Gandhi Multiple Myeloma Cell Killing by Depletion of the MET Receptor Tyrosine Kinase Cancer Res., October 15, 2007; 67(20): 9913 - 9920. [Abstract] [Full Text] [PDF] E. Weingrill, A. Wolfler, D. Strunk, W. Linkesch, H. Sill, and P. M. Liebmann Roscovitine in B-chronic lymphocytic leukemia cells: high apoptosis-inducing efficacy and synergism with alemtuzumab independent of the patients' pretreatment status Haematologica, September 1, 2007; 92(9): 1286 - 1288. [Abstract] [Full Text] [PDF] A. Muto, M. Hori, Y. Sasaki, A. Saitoh, I. Yasuda, T. Maekawa, T. Uchida, K. Asakura, T. Nakazato, T. Kaneda, et al. Emodin has a cytotoxic activity against human multiple myeloma as a Janus-activated kinase 2 inhibitor Mol. Cancer Ther., March 1, 2007; 6(3): 987 - 994. [Abstract] [Full Text] [PDF] W. DePinto, X.-J. Chu, X. Yin, M. Smith, K. Packman, P. Goelzer, A. Lovey, Y. Chen, H. Qian, R. Hamid, et al. In vitro and in vivo activity of R547: a potent and selective cyclin-dependent kinase inhibitor currently in phase I clinical trials. Mol. Cancer Ther., November 1, 2006; 5(11): 2644 - 2658. [Abstract] [Full Text] [PDF] L. B. Baughn, M. Di Liberto, K. Wu, P. L. Toogood, T. Louie, R. Gottschalk, R. Niesvizky, H. Cho, S. Ely, M. A.S. Moore, et al. A novel orally active small molecule potently induces g1 arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6. Cancer Res., August 1, 2006; 66(15): 7661 - 7667. [Abstract] [Full Text] [PDF] N. Gao, L. Kramer, M. Rahmani, P. Dent, and S. Grant The Three-Substituted Indolinone Cyclin-Dependent Kinase 2 Inhibitor 3-[1-(3H-Imidazol-4-yl)-meth-(Z)-ylidene]-5-methoxy-1,3-dihydro-indol-2-one (SU9516) Kills Human Leukemia Cells via Down-Regulation of Mcl-1 through a Transcriptional Mechanism Mol. Pharmacol., August 1, 2006; 70(2): 645 - 655. [Abstract] [Full Text] [PDF] G. I. Shapiro Cyclin-Dependent Kinase Pathways As Targets for Cancer Treatment J. Clin. Oncol., April 10, 2006; 24(11): 1770 - 1783. [Abstract] [Full Text] [PDF] A. Holleman, M. L. den Boer, R. X. de Menezes, M. H. Cheok, C. Cheng, K. M. Kazemier, G. E. Janka-Schaub, U. Gobel, U. B. Graubner, W. E. Evans, et al. The expression of 70 apoptosis genes in relation to lineage, genetic subtype, cellular drug resistance, and outcome in childhood acute lymphoblastic leukemia Blood, January 15, 2006; 107(2): 769 - 776. [Abstract] [Full Text] [PDF] D.P. LANE Exploiting the p53 Pathway for the Diagnosis and Therapy of Human Cancer Cold Spring Harb Symp Quant Biol, January 1, 2005; 70(0): 489 - 497. [Abstract] [PDF]

	Copyright © 2005 by American Society of Hematology         Online ISSN: 1528-0020