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Imatinib mesylate‐resistant human chronic myelogenous leukemia cell lines exhibit high sensitivity to the phytoalexin resveratrol
Author(s) -
Puissant Alexandre,
Grosso Sebastien,
Jacquel Arnaud,
Belhacene Nathalie,
Colosetti Pascal,
Cassuto JillPatrice,
Auberger Patrick
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.07-101394
Subject(s) - resveratrol , phytoalexin , chronic myelogenous leukemia , imatinib mesylate , apoptosis , imatinib , leukemia , viability assay , cancer research , clonogenic assay , chemistry , pharmacology , biology , immunology , biochemistry , myeloid leukemia
Imatinib is successfully used in the treat ment of chronic myelogenous leukemia (CML), and the main mechanisms of resistance in refractory patients are now partially understood. In the present study, we investigated the mechanism of action of resveratrol in imatinib‐sensitive (IM‐S) and ‐resistant (IM‐R) CML cell lines. Resveratrol induced loss of viability and apopto sis in IM‐S and IM‐R in a time‐ and dose‐dependent fashion. Inhibition of cell viability was detected for concentrations of resveratrol as low as 5 μ,M, and the IC 50 values for viability, clonogenic assays, apoptosis, and erythroid differentiation were in the 10–25 μ,M range. The effect of imatinib and resveratrol was additive in IM‐S but not in IM‐R clones in which the resveratrol effect was already maximal. The effect of resveratrol on apoptosis was partially rescued by zVAD‐ fmk, suggesting a caspase‐independent contribution. Resveratrol action was independent of BCR‐ABL ex pression and phosphorylation, and in agreement was additive to BCR‐ABL silencing. Finally, phytoalexin inhibited the growth of BaF3 cells expressing mutant BCR‐ABL proteins found in resistant patients, including the multiresistant T315I mutation. Our findings show that resveratrol induces apoptosis, caspase‐inde‐ pendent death, and differentiation that collectively contribute to the specific elimination of CML cells. Resveratrol should provide therapeutic benefits in IM‐R patients and in other hematopoietic malignancies.— Puissant, A., Grosso, S., Jacquel, A., Belhacene, N., Colosetti, P., Cassuto, J.‐P., Auberger, P. Imatinib mesylate‐resistant human chronic myelogenous leuke mia cell lines exhibit high sensitivity to the phytoalexin resveratrol. FASEB J. 22, 1894–1904 (2008)