Growth inhibition by STI571 in combination with radiation in human chronic myelogenous leukemia K562 cells.
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 (> or =24-h contact) retarded the growth of K562 cells and elicited reduction in the G(2)-phase content due to an efficient arrest in early S phase rather than to the disruption of the G(2) 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.
Huguet
Florence
F
Institut Curie, Centre de Recherche, Orsay, France.
Giocanti
Nicole
N
Hennequin
Christophe
C
Croisy
Martine
M
Touboul
Emmanuel
E
Favaudon
Vincent
V
D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001549:Benzamides; D049109:Cell Proliferation / Q000187:drug effects* / Q000528:radiation effects*; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D016922:Cellular Senescence / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D004353:Drug Evaluation, Preclinical; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000532:radiotherapy*; D009336:Necrosis / Q000209:etiology; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use; D016196:S Phase / Q000187:drug effects / Q000528:radiation effects
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D011838:Radiation-Sensitizing Agents; D000068877:Imatinib Mesylate