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Blood, 1 July 2007, Vol. 110, No. 1, pp. 313-322. Prepublished online as a Blood First Edition Paper on March 15, 2007; DOI 10.1182/blood-2006-10-050260. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2006-10-050260v1 110/1/313    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 Carew, J. S. Articles by Cleveland, J. L. Search for Related Content PubMed PubMed Citation Articles by Carew, J. S. Articles by Cleveland, J. L. Related Collections Neoplasia Apoptosis Oncogenes and Tumor Suppressors Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl–mediated drug resistance Jennifer S. Carew1, Steffan T. Nawrocki2, Charissa N. Kahue1,3, Hui Zhang4, Chunying Yang1, Linda Chung1, Janet A. Houghton2, Peng Huang4, Francis J. Giles5, and John L. Cleveland1,6 1 Departments of Biochemistry and 2 Oncology, St. Jude Children's Research Hospital, Memphis, TN; 3 Chaminade University, Honolulu, HI; 4 Departments of Molecular Pathology and 5 Leukemia, University of Texas M. D. Anderson Cancer Center, Houston; 6 Department of Cancer Biology, The Scripps Research Institute-Florida, Jupiter Novel therapeutic strategies are needed to address the emerging problem of imatinib resistance. The histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) is being evaluated for imatinib-resistant chronic myelogenous leukemia (CML) and has multiple cellular effects, including the induction of autophagy and apoptosis. Considering that autophagy may promote cancer cell survival, we hypothesized that disrupting autophagy would augment the anticancer activity of SAHA. Here we report that drugs that disrupt the autophagy pathway dramatically augment the antineoplastic effects of SAHA in CML cell lines and primary CML cells expressing wild-type and imatinib-resistant mutant forms of Bcr-Abl, including T315I. This regimen has selectivity for malignant cells and its efficacy was not diminished by impairing p53 function, another contributing factor in imatinib resistance. Disrupting autophagy by chloroquine treatment enhances SAHA-induced superoxide generation, triggers relocalization and marked increases in the lysosomal protease cathepsin D, and reduces the expression of the cathepsin-D substrate thioredoxin. Finally, knockdown of cathepsin D diminishes the potency of this combination, demonstrating its role as a mediator of this therapeutic response. Our data suggest that, when combined with HDAC inhibitors, agents that disrupt autophagy are a promising new strategy to treat imatinib-refractory patients who fail conventional therapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Rossi, E. R. Munarriz, S. Bartesaghi, M. Milanese, D. Dinsdale, M. A. Guerra-Martin, E. T. W. Bampton, P. Glynn, G. Bonanno, R. A. Knight, et al. Desmethylclomipramine induces the accumulation of autophagy markers by blocking autophagic flux J. 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Murphy The ARF Tumor Suppressor Can Promote the Progression of Some Tumors Cancer Res., December 1, 2008; 68(23): 9608 - 9613. [Abstract] [Full Text] [PDF] M. Degtyarev, A. De Maziere, C. Orr, J. Lin, B. B. Lee, J. Y. Tien, W. W. Prior, S. van Dijk, H. Wu, D. C. Gray, et al. Akt inhibition promotes autophagy and sensitizes PTEN-null tumors to lysosomotropic agents J. Cell Biol., October 6, 2008; 183(1): 101 - 116. [Abstract] [Full Text] [PDF] S. T. Nawrocki, J. S. Carew, K. H. Maclean, J. F. Courage, P. Huang, J. A. Houghton, J. L. Cleveland, F. J. Giles, and D. J. McConkey Myc regulates aggresome formation, the induction of Noxa, and apoptosis in response to the combination of bortezomib and SAHA Blood, October 1, 2008; 112(7): 2917 - 2926. [Abstract] [Full Text] [PDF] D. Buglio, G. V. Georgakis, S. Hanabuchi, K. Arima, N. M. Khaskhely, Y.-J. Liu, and A. Younes Vorinostat inhibits STAT6-mediated TH2 cytokine and TARC production and induces cell death in Hodgkin lymphoma cell lines Blood, August 15, 2008; 112(4): 1424 - 1433. [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. Han, W. Hou, L. A. Goldstein, C. Lu, D. B. Stolz, X.-M. Yin, and H. Rabinowich Involvement of Protective Autophagy in TRAIL Resistance of Apoptosis-defective Tumor Cells J. Biol. Chem., July 11, 2008; 283(28): 19665 - 19677. [Abstract] [Full Text] [PDF] J. S. Carew, S. T. Nawrocki, V. K. Reddy, D. Bush, J. E. Rehg, A. Goodwin, J. A. Houghton, R. A. Casero Jr, L. J. Marton, and J. L. 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