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PMID: 18574029 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Blood ·Vol. 112 ·No. 5 ·2008-09-01 ·Pages 1912-22

Trachootham D, Zhang H, Zhang W, Feng L, Du M, Zhou Y, Chen Z, Pelicano H, Plunkett W, Wierda WG, Keating MJ, Huang P

Abstract

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 beta-phenylethyl isothiocyanate (PEITC) with mean IC(50) values of 5.4 microM and 5.1 microM, respectively. Normal lymphocytes were significantly less sensitive to PEITC (IC(50) = 27 microM, 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.

MeSH Terms
Antineoplastic Agents/pharmacology Caspase 3/metabolism Cell Death/drug effects Cytochromes c/metabolism Drug Resistance, Neoplasm Glutathione/metabolism Glutathione Peroxidase/metabolism Humans In Vitro Techniques Isothiocyanates/pharmacology Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy,metabolism,pathology Lymphocytes/drug effects,metabolism,pathology Mitochondria/drug effects,metabolism Myeloid Cell Leukemia Sequence 1 Protein Oxidation-Reduction Proto-Oncogene Proteins c-bcl-2/metabolism Reactive Oxygen Species/metabolism Vidarabine/analogs & derivatives,pharmacology
Chemicals
Antineoplastic Agents Isothiocyanates Myeloid Cell Leukemia Sequence 1 Protein Proto-Oncogene Proteins c-bcl-2 Reactive Oxygen Species phenethyl isothiocyanate Cytochromes c Glutathione Peroxidase CASP3 protein, human Caspase 3 Vidarabine Glutathione fludarabine
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Trachootham Dunyaporn
Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Zhang Hui
Zhang Wan
Feng Li
Du Min
Zhou Yan
Chen Zhao
Pelicano Helene
Plunkett William
Wierda William G
Keating Michael J
Huang Peng
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
1528-0020
DOI
10.1182/blood-2008-04-149815
Published
2008-09-01
Epub
2008-00-23
Pages
1912-22
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC2518893
Subset
IM
Grants
NCI NIH HHS · R01 CA085563 · United States
NCI NIH HHS · CA16672 · United States
NCI NIH HHS · CA109041 · United States
NCI NIH HHS · R01 CA109041 · United States
NCI NIH HHS · CA100428 · United States
NCI NIH HHS · CA085563 · United States
NCI NIH HHS · R01 CA100428 · United States
NCI NIH HHS · P30 CA016672 · United States
External Links
PubMed source DOI: 10.1182/blood-2008-04-149815 PMC Full Text View journal details
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