Potentiation of DNA-Damage-Induced Cytotoxicity by G2Checkpoint Abrogators
Cell cycle checkpoints are activated in response to DNA-damage to ensure that accurate copies of the cellular genome are passed on to the next generation and to avoid replication and segregation of damaged DNA. These cellular control systems can be overcome by combining conventional DNA-damaging agents with compounds that target the cell cycle regulatory pathways, to enhance cytotoxicity. Tumor cells often comprise a corrupted G1 cell cycle checkpoint while the G2 cell cycle checkpoint is still intact. This review describes the concept of G2 checkpoint abrogation with recognized (methylxanthines, UCN-01) and novel G2 checkpoint abrogators to potentiate the cytotoxicity of DNA-damaging drugs and ionizing radiation. It illustrates the potential of G2 checkpoint abrogators to preferentially sensitize p53-mutated, treatment resistant tumor cells for genotoxic treatment. Identification of the targets of caffeine and UCN-01 to be key-players of the G2 checkpoint (ATM / ATR and Chk1, respectively) promoted the search for novel inhibitors of this checkpoint. Even though a direct causal link between G2 checkpoint abrogation and chemo- / radiosensitization is difficult to prove the multitude of these novel compounds validate that inhibition of critical elements of the G2 checkpoint (ATM / ATR-Chk1 / Chk2- CDC25C-cascade) potentiates the cytotoxicity of DNA-damaging agents.
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