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Centrosome aberrations and G₁ phase arrest after in vitro and in vivo treatment with the SRC/ABL inhibitor dasatinib

¹ III. Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim
² Clinical Cooperation Unit Molekulare Hämatologie/Onkologie, DKFZ and Department of Internal Medicine V, Universität Heidelberg, Heidelberg
³ MLL Münchner Leukämielabor GmbH, München, Germany

Correspondence: Alice Fabarius, III. Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Wiesbadener Straße 7-11, 68305 Mannheim, Germany. E-mail:alice.fabarius{at}med3.ma.uni-heidelberg.de

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.

Design and 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 G₁ 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 G₁ 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 G₁ phase arrest. INNO-406 was associated with centrosome aberrations and cell cycle arrest in G₁ phase.

Conclusions: Dasatinib blocks the G₁/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.

Key words: chronic myeloid leukemia, cytogenetics, centrosomes, spindles, tyrosine kinase inhibitors.