The mitotic spindle checkpoint is a critical determinant for topoisomerase-based chemotherapy.
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.
Vogel
Celia
C
Institute for Molecular Biology and Tumor Research (IMT), Philipps University Marburg, D-35037 Marburg, Germany.
Kienitz
Anne
A
Müller
Rolf
R
Bastians
Holger
H
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D016923:Cell Death; D045744:Cell Line, Tumor; D002469:Cell Separation; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D016195:G2 Phase; D006801:Humans; D008938:Mitosis; D015739:Nocodazole / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D008941:Spindle Apparatus; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D059003:Topoisomerase Inhibitors; D019076:Transgenes
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D059003:Topoisomerase Inhibitors; C054852:7-hydroxystaurosporine; D019311:Staurosporine; D015739:Nocodazole