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Prepublished online as a Blood First Edition Paper on December 27, 2002; DOI 10.1182/blood-2002-07-2283. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-07-2283v1 101/9/3628    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 Li, H. Y. Articles by Banker, D. E. Search for Related Content PubMed PubMed Citation Articles by Li, H. Y. Articles by Banker, D. E. Related Collections Oncogenes and Tumor Suppressors Signal Transduction Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 May 2003, Vol. 101, No. 9, pp. 3628-3634 NEOPLASIA Cholesterol-modulating agents kill acute myeloid leukemia cells and sensitize them to therapeutics by blocking adaptive cholesterol responses Henry Y. Li, Frederick R. Appelbaum, Cheryl L. Willman, Richard A. Zager, and Deborah E. Banker From the Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; the Department of Medicine, University of Washington, Seattle; and the Department of Pathology, University of New Mexico and UNM Cancer Center, Albuquerque. The mevalonate pathway produces many critical substances in cells, including sterols essential for membrane structure and isoprenoids vital to the function of many membrane proteins. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is a rate-limiting enzyme in the mevalonate pathway. Because cholesterol is a product of this pathway, HMG-CoA reductase inhibitors (statins) are used to treat hypercholesterolemia. Statins are also toxic to several malignancies, including acute myeloid leukemia (AML). Although this toxicity has been attributed to the inhibition of Ras/Rho isoprenylation, we have previously shown that statin toxicity in primary AML cells (AMLs) does not correlate with Ras isoprenylation or with activating Ras mutations. In other studies, we have shown that hypoxic and oxidant injuries induce cholesterol increments in renal tubule cells and that statins sensitize these cells to injury by blocking protective cholesterol responses. We now demonstrate that exposing particular AMLs to radiochemotherapy induces much greater cellular cholesterol increments than those seen in similarly treated normal bone marrow. Treatment of these AMLs with mevastatin or zaragozic acid (which inhibits cholesterol synthesis but not isoprenoid synthesis) attenuates the cholesterol increments and sensitizes cells to radiochemotherapy. The extent of toxicity is affected by the availability of extracellular lipoproteins, further suggesting that cellular cholesterol is critical to cell survival in particular AMLs. Because zaragozic acid does not inhibit isoprenoid synthesis, these data suggest that cholesterol modulation is an important mechanism whereby statins exert toxic effects on some AMLs and that cholesterol modulators may improve therapeutic ratios in AML by impacting cholesterol-dependent cytoresistance. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Woodard, A. Sassano, N. Hay, and L. C. Platanias Statin-Dependent Suppression of the Akt/Mammalian Target of Rapamycin Signaling Cascade and Programmed Cell Death 4 Up-Regulation in Renal Cell Carcinoma Clin. Cancer Res., July 15, 2008; 14(14): 4640 - 4649. [Abstract] [Full Text] [PDF] C. M. Shachaf, O. D. Perez, S. Youssef, A. C. Fan, S. Elchuri, M. J. Goldstein, A. E. Shirer, O. Sharpe, J. Chen, D. J. Mitchell, et al. 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