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Research Articles: Therapeutics, Targets, and Development

Growth inhibition by STI571 in combination with radiation in human chronic myelogenous leukemia K562 cells

¹ Institut Curie, Centre de Recherche; ² Institut National de la Santé et de la Recherche Médicale, U612; ³ Centre National de la Recherche Scientifique, UMR176, Orsay, France; and ⁴ AP-HP, Hôpital Tenon, Service d'Oncologie-Radiothérapie; and ⁵ AP-HP, Hôpital Saint Louis, Service de Cancérologie-Radiothérapie, Paris, France

Requests for reprints: Vincent Favaudon, Institut National de la Santé et de la Recherche Médicale U612, Institut Curie-Recherche, Bât., 110-112, Centre Universitaire, 91405 Orsay Cedex, France. Phone: 33-169863188; Fax: 33-169863187. E-mail: vincent.favaudon{at}curie.fr

Abstract

Altered radiation responses by STI571 (Imatinib, Glivec), a specific inhibitor of the tyrosine kinase activity of Bcr-Abl, was assessed in K562 chronic myelogenous leukemia cells using growth inhibition and colony formation assays. Flow cytometry, Western blotting, and microscope observation were used to determine cell cycle redistribution, erythroid differentiation, apoptosis, necrosis, senescence, and expression and phosphorylation of effectors downstream from Bcr-Abl as endpoints. STI571 (24-h contact) retarded the growth of K562 cells and elicited reduction in the G₂-phase content due to an efficient arrest in early S phase rather than to the disruption of the G₂ checkpoint as confirmed by analysis of Lyn and CDK1 phosphorylation. STI571 brought about the inhibitory dephosphorylation of Bcr-Abl and STAT5, but the expression of DNA-PKcs and Rad51 was unaffected and the interaction between radiation and STI571 was strictly additive with regard to induction of apoptosis. Overall STI571 interacted cooperatively with radiation to retard the growth of K562 cells but did not affect intrinsic radiosensitivity. However, STI571 and radiation acted antagonistically with each other with regard to induction of senescence and erythroid differentiation. [Mol Cancer Ther 2008;7(2):398–406]

Grant support: Fondation pour la Recherche Médicale (F. Huguet), Institut National de la Santé et de la Recherche Médicale, and Institut Curie.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: F. Huguet and N. Giocanti equally contributed to this study.

⁶ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 8/30/07; accepted 12/19/07.