title: Imatinib mesylate-resistant human chronic myelogenous leukemia cell lines exhibit high sensitivity to the phytoalexin resveratrol.
abstract: Imatinib is successfully used in the treatment 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 apoptosis 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 microM, and the IC(50) values for viability, clonogenic assays, apoptosis, and erythroid differentiation were in the 10-25 microM 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 expression 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-independent 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.
authors.affiliation: INSERM U526, Nice, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Puissant
authors.forename: Sebastien
authors.initials: S
authors.lastname: Grosso
authors.forename: Arnaud
authors.initials: A
authors.lastname: Jacquel
authors.forename: Nathalie
authors.initials: N
authors.lastname: Belhacene
authors.forename: Pascal
authors.initials: P
authors.lastname: Colosetti
authors.forename: Jill-Patrice
authors.initials: JP
authors.lastname: Cassuto
authors.forename: Patrick
authors.initials: P
authors.lastname: Auberger
mesh_terms: D000972:Antineoplastic Agents, Phytogenic; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D020169:Caspases; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D013267:Stilbenes; D000068877:Imatinib Mesylate; D020169:Caspases; D000077185:Resveratrol