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Blood, 1 September 2007, Vol. 110, No. 5, pp. 1656-1663. Prepublished online as a Blood First Edition Paper on May 17, 2007; DOI 10.1182/blood-2007-03-081240. This Article Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2007-03-081240v1 110/5/1656    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 Tai, Y.-T. Articles by Anderson, K. C Search for Related Content PubMed PubMed Citation Articles by Tai, Y.-T. Articles by Anderson, K. C Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 21, 2007 Accepted May 15, 2007 Targeting MEK induces myeloma cell cytotoxicity and inhibits osteoclastogenesis Yu-Tzu Tai*, Mariateresa Fulciniti, Teru Hideshima, Weihua Song, Merav Leiba, Xian-Feng Li, Matthew Rumizen, Peter Burger, Aileen Morrison, Klaus Podar, Dharminder Chauhan, Pierfrancesco Tassone, Paul Richardson, Nikhil C Munshi, Irene Ghobrial, and Kenneth C Anderson The Jerome Lipper Multiple Myeloma Center, Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States Veterans Administration Boston Health Care System, Harvard Medical School, Boston, MA, United States * Corresponding author; email: yu-tzu_tai{at}dfci.harvard.edu. Activation of the extracellular signal-regulated kinase1/2 (ERK1/2) signaling cascade mediates human multiple myeloma (MM) growth and survival triggered by cytokines and adhesion to bone marrow stromal cells (BMSCs). Here, we examined the effect of AZD6244 (ARRY-142886), a novel and specific MEK1/2 inhibitor, on human MM cell growth in the bone marrow (BM) milieu. AZD6244 blocks constitutive and cytokine-stimulated ERK1/2 phosphorylation and inhibits proliferation and survival of human MM cell lines and patient MM cells, regardless of sensitivity to conventional chemotherapy. Importantly, AZD6244 (200 nM) induces apoptosis in patient MM cells even in the presence of exogenous interleukin-6 or BMSCs associated with triggering of caspase 3 activity. AZD6244 sensitizes MM cells to both conventional (dexamethasone) and novel (perifosine, lenalidomide, and bortezomib) therapies. AZD6244 downregulates the expression/secretion of osteoclast (OC)-activating factors from MM cells, and inhibits in vitro differentiation of MM patient PBMCs to OCs induced by ligand for receptor activator of NF-B (RANKL) and macrophage-colony stimulating factor (M-CSF). Finally, AZD6244 inhibits tumor growth and prolongs survival in vivo in a human plasmacytoma xenograft model. Taken together, these results show that AZD6244 targets both MM cells and OCs in the BM microenvironment, providing the preclinical framework for clinical trials to improve patient outcome in MM. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: MEK inhibitor: the MM magic bullet? Bruno Quesnel Blood 2007 110: 1402-1403. [Full Text] [PDF] This article has been cited by other articles: M. Rahmani, A. Anderson, J. R. Habibi, T. R. Crabtree, M. Mayo, H. Harada, A. Ferreira-Gonzalez, P. Dent, and S. Grant The BH3-only protein Bim plays a critical role in leukemia cell death triggered by concomitant inhibition of the PI3K/Akt and MEK/ERK1/2 pathways Blood, November 12, 2009; 114(20): 4507 - 4516. [Abstract] [Full Text] [PDF] Y.-T. Tai, E. Soydan, W. Song, M. Fulciniti, K. Kim, F. Hong, X.-F. Li, P. Burger, M. J. Rumizen, S. Nahar, et al. CS1 promotes multiple myeloma cell adhesion, clonogenic growth, and tumorigenicity via c-maf-mediated interactions with bone marrow stromal cells Blood, April 30, 2009; 113(18): 4309 - 4318. [Abstract] [Full Text] [PDF] P. Lunghi, N. Giuliani, L. Mazzera, G. Lombardi, M. Ricca, A. Corradi, A. M. Cantoni, L. Salvatore, R. Riccioni, A. Costanzo, et al. Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways Blood, September 15, 2008; 112(6): 2450 - 2462. [Abstract] [Full Text] [PDF] Y. Dai, S. Chen, X.-Y. Pei, J. A. Almenara, L. B. Kramer, C. A. Venditti, P. Dent, and S. Grant Interruption of the Ras/MEK/ERK signaling cascade enhances Chk1 inhibitor-induced DNA damage in vitro and in vivo in human multiple myeloma cells Blood, September 15, 2008; 112(6): 2439 - 2449. [Abstract] [Full Text] [PDF] Y.-T. Tai, M. Dillon, W. Song, M. Leiba, X.-F. Li, P. Burger, A. I. Lee, K. Podar, T. Hideshima, A. G. Rice, et al. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu Blood, August 15, 2008; 112(4): 1329 - 1337. [Abstract] [Full Text] [PDF] B. B. Friday, C. Yu, G. K. Dy, P. D. Smith, L. Wang, S. N. Thibodeau, and A. A. Adjei BRAF V600E Disrupts AZD6244-Induced Abrogation of Negative Feedback Pathways between Extracellular Signal-Regulated Kinase and Raf Proteins Cancer Res., August 1, 2008; 68(15): 6145 - 6153. [Abstract] [Full Text] [PDF] Z. Chen, J. L. Ricker, P. S. Malhotra, L. Nottingham, L. Bagain, T. L. Lee, N. T. Yeh, and C. Van Waes Differential bortezomib sensitivity in head and neck cancer lines corresponds to proteasome, nuclear factor-{kappa}B and activator protein-1 related mechanisms Mol. Cancer Ther., July 1, 2008; 7(7): 1949 - 1960. [Abstract] [Full Text] [PDF]

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