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Blood, 15 August 2005, Vol. 106, No. 4, pp. 1400-1406. Prepublished online as a Blood First Edition Paper on May 5, 2005; DOI 10.1182/blood-2005-03-0929. This Article Full Text (PDF) All Versions of this Article: 2005-03-0929v1 106/4/1400    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 Avellino, R. Articles by Romano, M. F Search for Related Content PubMed PubMed Citation Articles by Avellino, R. Articles by Romano, M. F Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 7, 2005 Accepted April 22, 2005 Rapamycin Stimulates Apoptosis of Childhood Acute Lymphoblastic Leukemia Cells Raffaella Avellino, Simona Romano, Rosanna Parasole, Rita Bisogni, Annalisa Lamberti, Vincenzo Poggi, Salvatore Venuta, and Maria F Romano* Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy Department of Pediatric Onco-Hematology, AORN Pausilipon, Naples, Italy Department of Clinical and Experimental Medicine, 'Magna Graecia' University, Catanzaro, Italy * Corresponding author; email: romano{at}dbbm.unina.it. The PI3k/Akt pathway has been implicated in childhood acute lymphoblastic leukemia (ALL). Because rapamycin suppresses the oncogenic processes sustained by PI3k/Akt, we investigated whether rapamycin affects blast survival. We found that rapamycin induces apoptosis of blasts in 56% of the bone marrow samples analyzed. Using the PI3k inhibitor wortmannin, we show that the PI3k/Akt pathway is involved in blast survival. Moreover, rapamycin increased doxorubicin-induced apoptosis even in non-responder samples. Anthracyclines activate NF-B, and disruption of this signaling pathway increases the efficacy of apoptogenic stimuli. Rapamycin inhibited doxorubicin-induced NF-B in ALL samples. Using an siRNA approach, we demonstrate that FKBP51, a large immunophilin inhibited by rapamycin, is essential for drug-induced NF-B-activation in human leukemia. Furthermore, rapamycin did not increase doxorubicin-induced apoptosis when NF-B was over-expressed. In conclusion, rapamycin targets two pathways that are crucial for cell survival and chemoresistance of malignant lymphoblasts, i.e PI3k/Akt through mTOR and NF-B through FKBP51, suggesting that the drug could be beneficial in the treatment of childhood ALL. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. Crazzolara, A. Cisterne, M. Thien, J. Hewson, R. Baraz, K. F. Bradstock, and L. J. Bendall Potentiating effects of RAD001 (Everolimus) on vincristine therapy in childhood acute lymphoblastic leukemia Blood, April 2, 2009; 113(14): 3297 - 3306. [Abstract] [Full Text] [PDF] Z. Li, G. Beutel, M. Rhein, J. Meyer, C. Koenecke, T. Neumann, M. Yang, J. Krauter, N. von Neuhoff, M. Heuser, et al. High-affinity neurotrophin receptors and ligands promote leukemogenesis Blood, February 26, 2009; 113(9): 2028 - 2037. [Abstract] [Full Text] [PDF] D. S. Levy, J. A. Kahana, and R. Kumar AKT inhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines Blood, February 19, 2009; 113(8): 1723 - 1729. [Abstract] [Full Text] [PDF] E. Pencreach, E. Guerin, C. Nicolet, I. Lelong-Rebel, A.-C. Voegeli, P. Oudet, A. K. Larsen, M.-P. Gaub, and D. Guenot Marked Activity of Irinotecan and Rapamycin Combination toward Colon Cancer Cells In vivo and In vitro Is Mediated through Cooperative Modulation of the Mammalian Target of Rapamycin/Hypoxia-Inducible Factor-1{alpha} Axis Clin. Cancer Res., February 15, 2009; 15(4): 1297 - 1307. [Abstract] [Full Text] [PDF] K. A. Duthie, L. C. Osborne, L. J. Foster, and N. Abraham Proteomics Analysis of Interleukin (IL)-7-induced Signaling Effectors Shows Selective Changes in IL-7R{alpha}449F Knock-in T Cell Progenitors Mol. Cell. Proteomics, October 1, 2007; 6(10): 1700 - 1710. [Abstract] [Full Text] [PDF] E. Peponi, E. Drakos, G. Reyes, V. Leventaki, G. Z. Rassidakis, and L. J. Medeiros Activation of Mammalian Target of Rapamycin Signaling Promotes Cell Cycle Progression and Protects Cells from Apoptosis in Mantle Cell Lymphoma Am. J. Pathol., December 1, 2006; 169(6): 2171 - 2180. [Abstract] [Full Text] [PDF] L. F. Costa, M. Balcells, E. R. Edelman, L. M. Nadler, and A. A. Cardoso Proangiogenic stimulation of bone marrow endothelium engages mTOR and is inhibited by simultaneous blockade of mTOR and NF-{kappa}B Blood, January 1, 2006; 107(1): 285 - 292. [Abstract] [Full Text] [PDF]

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