Pharmacological inhibition of c-Abl compromises genetic stability and DNA repair in Bcr-Abl-negative cells.
Imatinib inhibits the kinase activity of Bcr-Abl and is currently the most effective drug for treatment of chronic myeloid leukemia (CML). Imatinib also blocks c-Abl, a physiological tyrosine kinase activated by a variety of stress signals including damaged DNA. We investigated the effect of pharmacological inhibition of c-Abl on the processing of irradiation-induced DNA damage in Bcr-Abl-negative cells. Cell lines and peripheral blood mononuclear cells (PBMCs) from healthy volunteers were treated with imatinib or dasatinib before gamma-irradiation. Inhibition of c-Abl caused an enhanced irradiation-induced mutation frequency and slowdown of DNA repair, whereas imatinib was ineffective in cells expressing a T315I variant of c-Abl. Mutation frequency and repair kinetics were also studied in c-Abl-/- murine embryonic fibroblasts (MEFs) retransfected with wild-type c-Abl (wt-Abl) or a kinase-defect variant of Abl (KD-Abl). Enhanced mutation frequency as well as delayed DNA repair was observed in cells expressing KD-Abl. These data indicate that pharmacological inhibition of c-Abl compromises DNA-damage response.
Fanta
S
S
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany.
Sonnenberg
M
M
Skorta
I
I
Duyster
J
J
Miething
C
C
Aulitzky
W E
WE
van der Kuip
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D002869:Chromosome Aberrations; D004249:DNA Damage; D004260:DNA Repair; D000069439:Dasatinib; D005347:Fibroblasts / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D010879:Piperazines / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl; D000069439:Dasatinib