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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.

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NEOPLASIA

Effective elimination of fludarabine-resistant CLL cells by PEITC through a redox-mediated mechanism

Dunyaporn Trachootham13, Hui Zhang1,2, Wan Zhang1,2, Li Feng1, Min Du4, Yan Zhou1, Zhao Chen1,2, Helene Pelicano1, William Plunkett5, William G. Wierda6, Michael J. Keating6, and Peng Huang1,2

1 Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston; 2 The University of Texas Graduate School of Biomedical Sciences at Houston; 3 Faculty of Dentistry, Thammasat University (Rangsit Campus), Pathum-thani, Thailand; and 4 Children's Cancer Hospital, 5 Department of Experimental Therapeutics, and 6 Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia, and resistance to fludarabine-based therapies is a major challenge in CLL treatment. Because CLL cells are 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 subjects (n = 12), we showed that both fludarabine-resistant and -sensitive CLL cells were highly sensitive to β-phenylethyl isothiocyanate (PEITC) with mean IC50 values of 5.4 µM and 5.1 µM, respectively. Normal lymphocytes were significantly less sensitive to PEITC (IC50 = 27 µM, P < .001). 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.


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