The Biology Behind To Arrest or Not To G2-M Cell-Cycle Arrest

Introduction Cells transverse the cell-cycle in several well-controlled phases (1). In the G1 phase, cells commit to enter the cell-cycle and prepare to duplicate their DNA in S phase. After S phase, cells enter the G2 phase, where repair might occur along with preparation for mitosis in M phase. In the M phase, chromatids and daughter cells separate. After M phase, the cells can enter G1 or G0, a quiescent phase. Entry into each phase of the cell-cycle is carefully regulated by receptor collectives, termed cell-cycle checkpoints. One theme emerging in drug discovery is to develop agents that target the cell-cycle checkpoints that are responsible for the control of cell-cycle phase progression. It is clear that the cell-cycle checkpoints can regulate the quality and rate of cell division; agents are now under development that either increase or decrease the degree of checkpoint arrest (2–8). For example, defects in the G1 arrest checkpoint may lead a cancer cell to enhanced proliferation, and efforts to correct these problems may slow growth and induce cell death. Defects in the G2-M arrest checkpoint may allow a damaged cell to enter mitosis and undergo apoptosis, and efforts to enhance this effect may increase the cytotoxicity of chemotherapy. Alternatively, efforts to increase G2-M arrest have also been associated with enhanced apoptosis. With a focus on the G2-M checkpoint, Tyagi et al. (9) studied an agent capable of altering G2-M cell-cycle checkpoint regulators and brought to light several questions, including the importance of enhancing cell-cycle checkpoint arrest compared with abrogation, what regulators should be targeted and the real contribution of checkpoint modulation to cytotoxicity and synergy.