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Prepublished online as a Blood First Edition Paper on February 27, 2003; DOI 10.1182/blood-2002-08-2391. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-08-2391v1 101/12/4990    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 Sturlan, S. Articles by Bachleitner-Hofmann, T. Search for Related Content PubMed PubMed Citation Articles by Sturlan, S. Articles by Bachleitner-Hofmann, T. Related Collections Neoplasia Apoptosis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 June 2003, Vol. 101, No. 12, pp. 4990-4997 NEOPLASIA Docosahexaenoic acid enhances arsenic trioxide–mediated apoptosis in arsenic trioxide–resistant HL-60 cells Sanda Sturlan, Melanie Baumgartner, Erich Roth, and Thomas Bachleitner-Hofmann From the Surgical Research Laboratories, Department of Surgery, University Hospital Vienna, Austria. Recent reports indicate a broad spectrum of antileukemic activity for arsenic trioxide (As2O3) due to its ability to induce apoptosis via intracellular production of reactive oxygen species (ROS). Despite its potent apoptotic mechanism, As2O3 is not equally effective in all leukemic cells, which has prompted a search for agents enhancing As2O3 efficacy. Recently, evidence has been gathered that the polyunsaturated fatty acid docosahexaenoic acid (DHA) may sensitize tumor cells to ROS-inducing anticancer agents. The aim of our investigation was to evaluate whether DHA enhances As2O3-mediated apoptosis in As2O3-resistant HL-60 cells. While 1 µM As2O3 or 25 µM DHA reduced cell viability to 85.8% ± 2.9% and 69.2% ± 3.6%, combined treatment with As2O3 and DHA reduced viability to 13.0% ± 9.9% with a concomitant increase of apoptosis. Apoptotic cell death was preceded by collapse of the mitochondrial membrane potential, increased expression of proapoptotic B-cell lymphoma protein-2–associated X protein (Bax), and caspase-3 activation. Importantly, the combined effect of As2O3 and DHA was associated with increased production of intracellular ROS and toxic lipid peroxidation products and was abolished by the antioxidant vitamin E or when oleic acid (a nonperoxidizable fatty acid) was used in place of DHA. Intracellular ROS and toxic lipid peroxidation products most likely constitute the key mediators contributing to the combined effect of As2O3 and DHA. Our data provide the first evidence that DHA may help to extend the therapeutic spectrum of As2O3 and suggest that the combination of As2O3 and DHA could be more broadly applied in leukemia therapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Brown, M. Bellon, and C. Nicot Emodin and DHA potently increase arsenic trioxide interferon-{alpha}-induced cell death of HTLV-I-transformed cells by generation of reactive oxygen species and inhibition of Akt and AP-1 Blood, February 15, 2007; 109(4): 1653 - 1659. [Abstract] [Full Text] [PDF] W.-Q. Ding, B. Liu, J. L. Vaught, R. D. Palmiter, and S. E. Lind Clioquinol and docosahexaenoic acid act synergistically to kill tumor cells. Mol. Cancer Ther., July 1, 2006; 5(7): 1864 - 1872. [Abstract] [Full Text] [PDF] Z. Diaz, M. Colombo, K. K. Mann, H. Su, K. N. Smith, D. S. Bohle, H. M. Schipper, and W. H. Miller Jr Trolox selectively enhances arsenic-mediated oxidative stress and apoptosis in APL and other malignant cell lines Blood, February 1, 2005; 105(3): 1237 - 1245. [Abstract] [Full Text] [PDF] M. A. S. Khan, H. Oubrahim, and E. R. Stadtman Inhibition of apoptosis in acute promyelocytic leukemia cells leads to increases in levels of oxidized protein and LMP2 immunoproteasome PNAS, August 10, 2004; 101(32): 11560 - 11565. [Abstract] [Full Text] [PDF]

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