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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 (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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 4, 2006 Accepted March 9, 2007 Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr- Abl-mediated drug resistance Jennifer S. Carew, Steffan T. Nawrocki, Charissa N. Kahue, Hui Zhang, Chunying Yang, Linda Chung, Janet A. Houghton, Peng Huang, Francis J. Giles, and John L. Cleveland* Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN, United States Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, United States Chaminade University, Honolulu, HI, United States Department of Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States Department of Cancer Biology, The Scripps Research Institute-Florida, Jupiter, FL, United States * Corresponding author; email: jcleve{at}scripps.edu. 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 anti-neoplastic 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 that 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. Cell Sci., September 15, 2009; 122(18): 3330 - 3339. [Abstract] [Full Text] [PDF] E. White and R. S. DiPaola The Double-Edged Sword of Autophagy Modulation in Cancer Clin. Cancer Res., September 1, 2009; 15(17): 5308 - 5316. [Abstract] [Full Text] [PDF] L. Ellis, M. Bots, R. K. Lindemann, J. E. Bolden, A. Newbold, L. A. Cluse, C. L. Scott, A. Strasser, P. Atadja, S. W. Lowe, et al. 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