SEARCH:   Advanced

Blood, 1 May 2007, Vol. 109, No. 9, pp. 4006-4015. Prepublished online as a Blood First Edition Paper on January 11, 2007; DOI 10.1182/blood-2006-09-045039. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-09-045039v1 109/9/4006    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 Nguyen, T. K. Articles by Grant, S. Search for Related Content PubMed PubMed Citation Articles by Nguyen, T. K. Articles by Grant, S. Related Collections Neoplasia Oncogenes and Tumor Suppressors Signal Transduction Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA MEK1/2 inhibitors sensitize Bcr/Abl+ human leukemia cells to the dual Abl/Src inhibitor BMS-354/825 Tri K. Nguyen1, Mohamed Rahmani1, Hisashi Harada1, Paul Dent2, and Steven Grant1,2,3 Departments of1 Medicine 2 Biochemistry, and 3 Pharmacology, Virginia Commonwealth University/Massey Cancer Center, Richmond, VA Interactions between MEK1/2 inhibitors and the dual Abl/Src kinase inhibitor dasatinib (BMS-354825) were examined in chronic myeloid leukemia (CML) cell lines and primary specimens. Cotreatment of K562 or LAMA cells with subtoxic or marginally toxic concentrations of PD184352 (or U0126) and dasatinib synergistically potentiated mitochondrial damage, caspase activation, and apoptosis. Similar interactions were observed in CD34+ cells from one CML patient–derived but not in a normal human CD34+ bone marrow cell specimen. These interactions were associated with multiple perturbations in survival signaling pathways, including inactivation of Bcr/Abl, STAT5, and ERK1/2; down-regulation of Bcl-xL and Mcl-1; and dephosphorylation/activation of Bim. They were also associated with BAX/BAK conformational change, mitochondrial dysfunction, and caspase activation. Bim knockdown by shRNA suppressed BAX and BAK conformational change and protected cells from dasatinib/PD184352 lethality. Conversely, K562 cells ectopically expressing Mcl-1 or Bcl-xL were significantly less susceptible to dasatinib/PD184352 toxicity. Notably, the dasatinib/PD184352 regimen was active against leukemic cells exhibiting various forms of imatinib mesylate resistance, including Bcr/Abl overexpression, Lyn activation, and several Bcr/Abl kinase domain mutations (eg, E255K, M351T), but not T315I. Together, these findings suggest that strategies combining dasatanib with MEK1/2 inhibitors warrant further investigation in Bcr/Abl+ malignancies, particularly in the setting of imatinib mesylate–resistant disease. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Comparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)–based mutagenesis screen: high efficacy of drug combinations Heather A. Bradeen, Christopher A. Eide, Thomas O'Hare, Kara J. Johnson, Stephanie G. Willis, Francis Y. Lee, Brian J. Druker, and Michael W. Deininger Blood 2006 108: 2332-2338. [Abstract] [Full Text] [PDF] This article has been cited by other articles: J. L. Snead, T. O'Hare, L. T. Adrian, C. A. Eide, T. Lange, B. J. Druker, and M. W. Deininger Acute dasatinib exposure commits Bcr-Abl-dependent cells to apoptosis Blood, October 15, 2009; 114(16): 3459 - 3463. [Abstract] [Full Text] [PDF] C. R. Geest and P. J. Coffer MAPK signaling pathways in the regulation of hematopoiesis J. Leukoc. Biol., August 1, 2009; 86(2): 237 - 250. [Abstract] [Full Text] [PDF] K. Kadohara, M. Nagumo, S. Asami, Y. Tsukumo, H. Sugimoto, M. Igarashi, K. Nagai, and T. Kataoka Caspase-8 Mediates Mitochondrial Release of Pro-apoptotic Proteins in a Manner Independent of Its Proteolytic Activity in Apoptosis Induced by the Protein Synthesis Inhibitor Acetoxycycloheximide in Human Leukemia Jurkat Cells J. Biol. Chem., February 27, 2009; 284(9): 5478 - 5487. [Abstract] [Full Text] [PDF] E. Marston, V. Weston, J. Jesson, E. Maina, C. McConville, A. Agathanggelou, A. Skowronska, K. Mapp, K. Sameith, J. E. Powell, et al. Stratification of pediatric ALL by in vitro cellular responses to DNA double-strand breaks provides insight into the molecular mechanisms underlying clinical response Blood, January 1, 2009; 113(1): 117 - 126. [Abstract] [Full Text] [PDF] D. Y. H. Hallaert, A. Jaspers, C. J. van Noesel, M. H. J. van Oers, A. P. Kater, and E. Eldering c-Abl kinase inhibitors overcome CD40-mediated drug resistance in CLL: implications for therapeutic targeting of chemoresistant niches Blood, December 15, 2008; 112(13): 5141 - 5149. [Abstract] [Full Text] [PDF] Y. Dai, S. Chen, C. A. Venditti, X.-Y. Pei, T. K. Nguyen, P. Dent, and S. Grant Vorinostat synergistically potentiates MK-0457 lethality in chronic myelogenous leukemia cells sensitive and resistant to imatinib mesylate Blood, August 1, 2008; 112(3): 793 - 804. [Abstract] [Full Text] [PDF] J. V. Melo and C. Chuah Novel Agents in CML Therapy: Tyrosine Kinase Inhibitors and Beyond Hematology, January 1, 2008; 2008(1): 427 - 435. [Abstract] [Full Text] [PDF] C. Mitchell, P. Kabolizadeh, J. Ryan, J. D. Roberts, A. Yacoub, D. T. Curiel, P. B. Fisher, M. P. Hagan, N. P. Farrell, S. Grant, et al. Low-Dose BBR3610 Toxicity in Colon Cancer Cells Is p53-Independent and Enhanced by Inhibition of Epidermal Growth Factor Receptor (ERBB1)-Phosphatidyl Inositol 3 Kinase Signaling Mol. Pharmacol., September 1, 2007; 72(3): 704 - 714. [Abstract] [Full Text] [PDF]

	Copyright © 2007 by American Society of Hematology         Online ISSN: 1528-0020