SEARCH:   Advanced

Blood, 15 May 2007, Vol. 109, No. 10, pp. 4415-4423. Prepublished online as a Blood First Edition Paper on January 30, 2007; DOI 10.1182/blood-2006-09-047076. This Article Full Text (PDF) All Versions of this Article: blood-2006-09-047076v1 109/10/4415    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 Dai, Y. Articles by Grant, S. Search for Related Content PubMed PubMed Citation Articles by Dai, Y. Articles by Grant, S. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 15, 2006 Accepted January 20, 2007 Statins synergistically potentiate 7-hydroxystaurosporine (UCN-01) lethality in human leukemia and myeloma cells by disrupting Ras farnesylation and activation Yun Dai, Payal Khanna, Shuang Chen, Xin-Yan Pei, Paul Dent, and Steven Grant* Dept of Medicine, Virginia Commonwealth University/Massey Cancer Center, Richmond, VA, United States Depts of Pharmacology and Radiation Oncology, Virginia Commonwealth University/Massey Cancer Center, Richmond, VA, United States Dept of Biochemistry, Virginia Commonwealth University/Massey Cancer Center, Richmond, VA, United States * Corresponding author; email: stgrant{at}hsc.vcu.edu. Interactions between UCN-01 and HMG-CoA reductase inhibitors (i.e., statins) have been examined in human leukemia and myeloma cells. Exposure of U937 and U266 cells to minimally toxic concentrations of UCN-01 and various statins (e.g., lovastatin, simvastatin, or fluvastatin) dramatically increased mitochondrial dysfunction, caspase activation, and apoptosis. Comparable effects were observed in other leukemia and myeloma cell lines as well as in primary AML blasts, but not in normal hematopoietic cells. Potentiation of UCN-01 lethality by lovastatin was associated with disruption of Ras prenylation and activation. These events were significantly attenuated by farnesyl pyrophosphate (FPP) but not by geranylgeranyl pyrophosphate (GGPP), implicating perturbations in farnesylation rather than geranylgeranylation in synergistic interactions. Co-exposure to statins and UCN-01 resulted in inactivation of ERK1/2 and Akt, accompanied by JNK activation. U266 cells ectopically expressing JNK1-APF, a dominant-negative JNK1 mutant, displayed significantly reduced susceptibility to lovastatin/UCN-01-mediated lethality. Moreover, transfection of U266 cells with constitutively activated H-Ras (Q61L) attenuated ERK1/2 inactivation and dramatically diminished the lethality of this regimen. Collectively, these findings indicate that HMG-CoA reductase inhibitors act through a Ras farnesylation-associated mechanism to induce signaling perturbations, particularly prevention of Ras and ERK1/2 activation, in UCN-01-treated cells, resulting in the synergistic induction of cell death. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. Hamed, W. Hawkins, C. Mitchell, D. Gilfor, G. Zhang, X.-Y. Pei, Y. Dai, M. P. Hagan, J. D. Roberts, A. Yacoub, et al. Transient exposure of carcinoma cells to RAS/MEK inhibitors and UCN-01 causes cell death in vitro and in vivo Mol. Cancer Ther., March 1, 2008; 7(3): 616 - 629. [Abstract] [Full Text] [PDF] X.-Y. Pei, Y. Dai, S. Tenorio, J. Lu, H. Harada, P. Dent, and S. Grant MEK1/2 inhibitors potentiate UCN-01 lethality in human multiple myeloma cells through a Bim-dependent mechanism Blood, September 15, 2007; 110(6): 2092 - 2101. [Abstract] [Full Text] [PDF]

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