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J. Biol. Chem., Vol. 280, Issue 6, 4025-4028, February 11, 2005

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The Mitotic Spindle Checkpoint Is a Critical Determinant for Topoisomerase-based Chemotherapy^*

Celia Vogel, Anne Kienitz, Rolf Müller, and Holger Bastians

From the Institute for Molecular Biology and Tumor Research (IMT), Philipps University Marburg, D-35037 Marburg, Germany

A novel strategy in cancer therapy is the induction of mitotic cell death by the pharmacological abrogation of cell cycle checkpoints. UCN-01 is such a compound that overrides the G₂ cell cycle arrest induced by DNA damage and forces cells into a deleterious mitosis. The molecular pathways leading to mitotic cell death are largely unknown although recent evidence indicates that mitotic cell death represents a special case of apoptosis. Here, we demonstrate that the mitotic spindle checkpoint is activated upon chemotherapeutic treatment with topoisomerase II poisons and UCN-01. Cells that are forced to enter mitosis in the presence of topoisomerase inhibition arrest transiently in a prometaphase like state. By using a novel pharmacological inhibitor of the spindle checkpoint and spindle checkpoint-deficient cells we show that the spindle checkpoint function is required for the mitotic arrest and, most importantly, for efficient induction of mitotic cell death. Thus, our results demonstrate that the mitotic spindle checkpoint is an important determinant for the outcome of a chemotherapy based on the induction of mitotic cell death. Its frequent inactivation in human cancer might contribute to the observed resistance of tumor cells to these chemotherapeutic drugs.

Received for publication, November 24, 2004 , and in revised form, December 13, 2004.

^* This work was supported by the Deutsche Forschungsgemeinschaft, the Deutsche Krebshilfe, and the P. E. Kempkes Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

To whom correspondence should be addressed: Philipps University Marburg, Inst. for Molecular Biology and Tumor Research (IMT), Emil-Mannkopff-Strasse 2, 35037 Marburg, Germany. Tel.: 49-6421-2863113; Fax: 49-6421-2865932; E-mail: bastians{at}imt.uni-marburg.de.

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