Centrosome aberrations and G1 phase arrest after in vitro and in vivo treatment with the SRC/ABL inhibitor dasatinib.
BACKGROUND
Dasatinib is a multitargeted inhibitor of ABL, the SRC family, and other tyrosine kinases. We sought to evaluate the effects of this drug on cell proliferation, centrosomes, mitotic spindles, and cell cycle progression in vitro and in vivo.


METHODS
Human dermal fibroblasts, Chinese hamster cells, human osteosarcoma cells, and blood and bone marrow mononuclear cells from 32 patients with chronic myeloid leukemia, gastrointestinal stromal tumor, and systemic mastocytosis as well as from six healthy individuals were investigated. The effects of dasatinib were compared with those of the ABL inhibitors imatinib and nilotinib, the SRC inhibitor PP2, and the ABL/LYN inhibitor INNO-406.


RESULTS
Dasatinib induced G(1) phase arrest in all cell lines and this was associated with a decline in cyclin D1 levels. In vitro, centrosomal aberrations, a decrease of mitotic spindles, and G(1) phase arrest were observed. In patients, centrosome alterations were found in a median of 17% (range, 10-22%) of cells with a decrease of spindles in 8/18 patients. In comparison, imatinib, nilotinib and PP2 led to centrosome aberrations without G(1) phase arrest. INNO-406 was associated with centrosome aberrations and cell cycle arrest in G(1) phase.


CONCLUSIONS
Dasatinib blocks the G(1)/S transition and inhibits cell growth. It induces centrosomal aberrations and a decrease of mitotic spindles. The effects suggest an involvement of SRC and ABL inhibition.
III. Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Wiesbadener Strasse 7-11, 68305 Mannheim, Germany. alice.fabarius@med3.ma.uni-heidelberg.de
Alice
A
Fabarius
Michelle
M
Giehl
Blanka
B
Rebacz
Alwin
A
Krämer
Oliver
O
Frank
Claudia
C
Haferlach
Peter
P
Duesberg
Rüdiger
R
Hehlmann
Wolfgang
W
Seifarth
Andreas
A
Hochhaus
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D016466:CHO Cells; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D018385:Centrosome / Q000187:drug effects*; D006224:Cricetinae; D003412:Cricetulus; D005347:Fibroblasts / Q000502:physiology*; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics*; D016313:Genes, abl / Q000187:drug effects*; D016391:Genes, src / Q000187:drug effects*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D012516:Osteosarcoma; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D012879:Skin Physiological Phenomena
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate