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¹ Laboratory of Molecular and Cellular Pharmacology, Department of Pharmaceutical Technology and Biochemistry, Gdansk University of Technology, Gdansk, Poland and ² Group of Molecular and Clinical Cancer Therapeutics, Institut National de la Sante et de la Recherche Medicale U673, Hôpital Saint-Antoine, and Université Pierre and Marie Curie, Paris, France

Requests for reprints: Andrzej Skladanowski, Laboratory of Molecular and Cellular Pharmacology, Department of Pharmaceutical Technology and Biochemistry, Gdansk University of Technology, Narutowicza Street 11/12, 80-952 Gdansk, Poland. Phone: 48-58-3471749; Fax: 48-58-3471144. E-mail: as{at}altis.chem.pg.gda.pl

In this study, we wanted to clarify the role of survivin-mediated survival signaling during G₂ and M in tumor cells treated with DNA-damaging agents. As a cellular model, we selected MOLT-4 human T-cell lymphoblastic leukemia cells that overexpress survivin and nonfunctional p53. Treatment with melphalan, a classic DNA-damaging agent, led to the induction of the DNA damage checkpoint and growth arrest in the G₂ phase of the cell cycle. Checkpoint abrogation by caffeine was accompanied by mitotic entry and rapid apoptotic cell death, whereas cells remaining in G₂ remained viable during the same time interval. Unexpectedly, when the spindle checkpoint was activated following G₂ abrogation, two different effects could be observed. If the microtubules of the melphalan-treated cells were destabilized by nocodazole, cells became arrested in prometaphase with low survivin levels and entered apoptosis. In contrast, if the microtubules of the melphalan-treated cells were stabilized by taxol, cells were still arrested in prometaphase, but apoptotic execution was inhibited. This effect is, most likely, directly mediated by survivin itself given its well-established antiapoptotic functions. In conclusion, depending on the way the spindle checkpoint was activated in cells with damaged DNA, cells could be either protected by survivin or die during mitosis. We suggest that the efficacy of DNA damage checkpoint abrogators used in combination with DNA-damaging agents may critically depend on whether DNA damage is able to invoke spindle checkpoint response and to activate survivin-associated survival signaling during mitosis. [Mol Cancer Ther 2005;4(12):2016–25]

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Note: A.K. Larsen and A. Skladanowski contributed equally to this work. P. Bozko was a fellow of the Marie Curie Training Site at the Institute Gustave-Roussy, Villejuif, France.

Received 5/ 2/05; revised 7/19/05; accepted 9/21/05.