Premium
Tumor cell‐specific cytotoxicity by targeting cell cycle checkpoints
Author(s) -
Warrener Robyn,
Beamish Heather,
Burgess Andrew,
Waterhouse Nigel J.,
Giles Nichole,
Fairlie David P.,
Gabrielli Brian
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-1003fje
Subject(s) - mitosis , cell cycle , cell cycle checkpoint , microbiology and biotechnology , histone deacetylase , g2 m dna damage checkpoint , histone deacetylase inhibitor , cancer research , histone deacetylase 5 , spindle checkpoint , cancer cell , cytotoxicity , biology , chemistry , histone , cell , spindle apparatus , cell division , cancer , biochemistry , in vitro , genetics , gene
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 G 2 ‐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 G 2 ‐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.