Tumor cell-selective cytotoxicity by targeting cell cycle checkpoints.
Cell cycle checkpoints act to protect cells from external stresses and internal errors that would compromise the integrity of the cell. Checkpoints are often defective in cancer cells. Drugs that target checkpoint mechanisms should therefore be selective for tumor cells that are defective for the drug-sensitive checkpoint. Histone deacetylase inhibitors typify this class of agents. They trigger a G2-phase checkpoint response in normal cells but are cytotoxic in tumor cells in which this checkpoint is defective. In this study, we investigated the molecular basis of the tumor-selective cytotoxicity of these drugs and demonstrated that it is due to the disruption of two cell cycle checkpoints. The first is the histone deacetylase inhibitor-sensitive G2-phase checkpoint, which is defective in drug-sensitive cells and permits cells to enter an aberrant mitosis. The second is the drug-dependent bypass of the mitotic spindle checkpoint that normally detects aberrant mitosis and blocks mitotic exit until the defect is rectified. The disruption of both checkpoints results in the premature exit of cells from an abortive mitosis followed by apoptosis. This study of histone deacetylase inhibitors demonstrates that drugs targeting cell cycle checkpoints can provide the selectivity and cytotoxicity desired in effective chemotherapeutic agents.
Warrener
Robyn
R
Cancer Biology Program, Centre for Immunology and Cancer Research, University of Queensland, Brisbane, Queensland. 4102, Australia.
Beamish
Heather
H
Burgess
Andrew
A
Waterhouse
Nigel J
NJ
Giles
Nichole
N
Fairlie
David
D
Gabrielli
Brian
B
D000970:Antineoplastic Agents / Q000737:chemistry / Q000633:toxicity*; D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000633:toxicity*; D016195:G2 Phase; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000633:toxicity*; D007700:Kinetics; D008954:Models, Biological; D008941:Spindle Apparatus / Q000187:drug effects
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C107648:azelaic bishydroxamic acid