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Blood, 1 September 2008, Vol. 112, No. 5, pp. 1912-1922. Prepublished online as a Blood First Edition Paper on June 23, 2008; DOI 10.1182/blood-2008-04-149815. This Article Full Text (PDF) Supplemental Table and Figures All Versions of this Article: blood-2008-04-149815v1 112/5/1912    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 Trachootham, D. Articles by Huang, P. Search for Related Content PubMed PubMed Citation Articles by Trachootham, D. Articles by Huang, P. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 9, 2008 Accepted May 31, 2008 Effective Elimination of Fludarabine-Resistant CLL Cells by PEITC through a Redox-Mediated Mechanism Dunyaporn Trachootham, Hui Zhang, Wan Zhang, Li Feng, Min Du, Yan Zhou, Zhao Chen, Helene Pelicano, William Plunkett, William G. Wierda, Michael J. Keating, and Peng Huang* Faculty of Dentistry, Thammasat University (Rangsit Campus), Pathum-thani, Thailand Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, United States The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, United States Children's Cancer Hospital, The University of Texas MD Anderson Cancer Center, Houston, United States Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States * Corresponding author; email: phuang{at}mdanderson.org. Chronic lymphocytic leukemia (CLL) is the most common adult leukemia, and resistance to fludarabine-based therapies is a major challenge in CLL treatment. Since CLL cells were known to have elevated levels of reactive oxygen species (ROS), we aimed to test a novel ROS-mediated strategy to eliminate fludarabine-resistant CLL cells based on this redox alteration. Using primary CLL cells and normal lymphocytes from patients (n=58) and healthy individuals (n=12), we showed that both fludarabine-resistant and sensitive CLL cells were highly sensitive to -Phenylethyl Isothiocyanate (PEITC) with the mean IC50 values of 5.4 and 5.1 µM, respectively. Normal lymphocytes were significantly less sensitive to PEITC (IC50=27 µM, p<0.0001). CLL cells exhibited intrinsically higher ROS level and lower cellular glutathione, which were shown to be the critical determinants of CLL sensitivity to PEITC. Exposure of CLL cells to PEITC induced severe glutathione depletion, ROS accumulation, and oxidation of mitochondrial cardiolipin leading to massive cell death. Such ROS stress also caused deglutathionylation of MCL1, followed by a rapid degradation of this cell survival molecule. Our study demonstrated that the natural compound PEITC is effective in eliminating fludarabine-resistant CLL cells through a redox-mediated mechanism with low toxicity to normal lymphocytes, and warrants further clinical evaluation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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