Mechanisms of mitotic cell death induced by chemotherapy-mediated G2 checkpoint abrogation.

Abstract

The novel concept of anticancer treatment termed "G(2) 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 G(2) 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 G(2) 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.

• Authors: Celia Vogel, Christian Hager, Holger Bastians
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 1 Pg. 339-45 (Jan 01 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17210716 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BIRC5 protein, human
• Calcium-Binding Proteins
• Cell Cycle Proteins
• Inhibitor of Apoptosis Proteins
• MAD2L1 protein, human
• Mad2 Proteins
• Microtubule-Associated Proteins
• Neoplasm Proteins
• Repressor Proteins
• Survivin
• 7-hydroxystaurosporine
• Doxorubicin
• AURKB protein, human
• Aurora Kinase B
• Aurora Kinases
• Protein Serine-Threonine Kinases
• CDC2 Protein Kinase
• Staurosporine

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects, physiology)
• Aurora Kinase B
• Aurora Kinases
• CDC2 Protein Kinase (antagonists & inhibitors, metabolism)
• Calcium-Binding Proteins (physiology)
• Cell Cycle Proteins (physiology)
• Doxorubicin (administration & dosage)
• Drug Synergism
• G2 Phase (drug effects, physiology)
• HeLa Cells
• Humans
• Inhibitor of Apoptosis Proteins
• Mad2 Proteins
• Microtubule-Associated Proteins (physiology)
• Mitosis (drug effects, physiology)
• Neoplasm Proteins (physiology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Repressor Proteins (physiology)
• Spindle Apparatus (drug effects, physiology)
• Staurosporine (administration & dosage, analogs & derivatives, pharmacology)
• Survivin