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Mechanisms of Mitotic Cell Death Induced by Chemotherapy-Mediated G₂ Checkpoint Abrogation

Institute for Molecular Biology and Tumor Research, Philipps University of Marburg, Marburg, Germany

Requests for reprints: Holger Bastians, Institute for Molecular Biology and Tumor Research, Philipps University of Marburg, Emil-Mannkopff-Strasse 2, D-35037 Marburg, Germany. Phone: 49-6421-2863113; Fax: 49-6421-2865932; E-mail: bastians{at}imt.uni-marburg.de.

The novel concept of anticancer treatment termed "G₂ checkpoint abrogation" aims to target p53-deficient tumor cells and is currently explored in clinical trials. The anticancer drug UCN-01 is used to abrogate a DNA damage–induced G₂ cell cycle arrest leading to mitotic entry and subsequent cell death, which is poorly defined as "mitotic cell death" or "mitotic catastrophe." We show here that UCN-01 treatment results in a mitotic arrest that requires an active mitotic spindle checkpoint, involving the function of Mad2, Bub1, BubR1, Mps1, Aurora B, and survivin. During the mitotic arrest, hallmark parameters of the mitochondria-associated apoptosis pathway become activated. Interestingly, this apoptotic response requires the spindle checkpoint protein Mad2, suggesting a proapoptotic function for Mad2. However, although survivin and Aurora B are also required for the mitotic arrest, both proteins are part of an antiapoptotic pathway that restrains the UCN-01–induced apoptosis by promoting hyperphosphorylation of Bcl-2 and by inhibiting the activation of Bax. Consequently, inhibition of the antiapoptotic pathway by genetic ablation of survivin or by pharmacologic inhibitors of Aurora B or cyclin-dependent kinase 1 lead to a significant enhancement of apoptosis and therefore act synergistically with UCN-01. Thus, by defining the mechanism of cell death on G₂ checkpoint abrogation we show a highly improved strategy for an anticancer treatment by the combined use of UCN-01 with abrogators of the survivin/Aurora B–dependent antiapoptotic pathway that retains the selectivity for p53-defective cancer cells. [Cancer Res 2007;67(1):339–45]

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