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Blood, 15 February 2008, Vol. 111, No. 4, pp. 2200-2210. Prepublished online as a Blood First Edition Paper on November 16, 2007; DOI 10.1182/blood-2006-11-055723. This Article Full Text (PDF) All Versions of this Article: blood-2006-11-055723v1 111/4/2200    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mayerhofer, M. Articles by Valent, P. Search for Related Content PubMed PubMed Citation Articles by Mayerhofer, M. Articles by Valent, P. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 2, 2006 Accepted November 5, 2007 Targeting of heat shock protein 32 (Hsp32) / heme oxygenase-1 (HO-1) in leukemic cells in chronic myeloid leukemia: a novel approach to overcome resistance against imatinib Matthias Mayerhofer*, Karoline V Gleixner, Julia Mayerhofer, Gregor Hoermann, Eva Jaeger, Karl J Aichberger, Rene G Ott, Khaled Greish, Hideaki Nakamura, Sophia Derdak, Puchit Samorapoompichit, Winfried F Pickl, Veronika Sexl, Harald Esterbauer, Ilse Schwarzinger, Christian Sillaber, Hiroshi Maeda, and Peter Valent Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria Department of Pharmacology, Medical University of Vienna, Vienna, Austria Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan Institute of Immunology, Medical University of Vienna, Vienna, Austria Institute of Histology and Embryology, Medical University of Vienna, Vienna, Austria * Corresponding author; email: matthias.mayerhofer{at}meduniwien.ac.at. Resistance towards imatinib and other BCR/ABL tyrosine kinase inhibitors remains an increasing clinical problem in the treatment of advanced stages of chronic myeloid leukemia (CML). We have recently identified the heat shock protein 32 (Hsp32) / heme oxygenase-1 (HO-1) as a BCR/ABL-dependent survival molecule in CML cells. We here show that silencing Hsp32/HO-1 in CML cells by an siRNA-approach results in induction of apoptosis. Moreover, targeting Hsp32/HO-1 by either pegylated zinc protoporphyrine (PEG-ZnPP) or styrene maleic acid-micelle-encapsulated ZnPP (SMA-ZnPP) resulted in growth inhibition of BCR/ABL-transformed cells. The effects of PEG-ZnPP and SMA-ZnPP were demonstrable in Ba/F3 cells carrying various imatinib-resistant mutants of BCR/ABL, including the T315I mutant, which exhibits resistance against all clinically available BCR/ABL tyrosine kinase inhibitors. Growth-inhibitory effects of PEG-ZnPP and SMA-ZnPP were also observed in the CML-derived human cell lines K562 and KU812 as well as in primary leukemic cells obtained from patients with freshly diagnosed CML or imatinib-resistant CML. Finally, Hsp32/HO-1-targeting compounds were found to synergize with either imatinib or nilotinib in producing growth inhibition in imatinib-resistant K562 cells and in Ba/F3 cells harbouring the T315I mutant of BCR/ABL. In summary, these data show that HO-1 is a promising novel target in imatinib-resistant CML. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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