G2 checkpoint abrogation and checkpoint kinase-1 targeting in the treatment of cancer

Abstract

Rigorous quality control steps, termed checkpoints, tightly regulate progression through the cell cycle. DNA-damaging chemotherapy and radiation activate functional cellular checkpoints. These checkpoints can facilitate DNA repair and promote cell death in unrepaired cells. There are at least three DNA damage checkpoints -at G1/S, S, and G2/M -as well as a mitotic spindle checkpoint. Most cancer cells harbour mutations in tumour suppressors and/or oncogenes, which impair certain cell checkpoints. Inhibiting the remaining cell checkpoints -particularly after exposure of cancer cells to chemotherapy and/or radiation -allows cell death, a strategy now being employed in cancer therapeutics. With our increasing knowledge of cell cycle regulation, many compounds have been developed to inhibit specific checkpoint components, particularly at the G2/M transition. One such target is checkpoint kinase-1 (Chk1). We review here the molecular framework of the cell cycle, the rationale for targeting Chk1, the preclinical concepts related to the development of Chk1 inhibitors, and the efficacy and safety results from Chk1 inhibitors now in phase I/II trials. British Journal of Cancer (2008) The cell cycle is organised into a series of dependent pathways, whereby the initiation of each event is dependent upon successful completion of previous events. In this way, replicating cells traverse the four distinct phases of the cell cycle consecutively: G1 followed by S, followed by G2 and, finally, M. This ordered progression is guarded by checkpoints capable of delaying the cell cycle in response to intra-or extracellular stressors. As part of the cell cycle surveillance system, the DNA damage and spindle checkpoints protect the cell from genomic instability. Checkpoints are important quality control measures that ensure the proper sequence of cell cycle events and allow cells to respond to DNA damage.Increasingly, checkpoint inhibition has become an area of novel drug development. In the setting of DNA damage, checkpoint inhibition leads to genomic instability, and subsequent cell death. The first checkpoint, found at the G1/S transition, is compromised in many malignant cells, due to mutations in various tumour suppressor genes, including retinoblastoma protein (Rb) and p53. Cells deficient in the G1 checkpoint are dependent on the S and G2 checkpoints for DNA repair. Checkpoint kinase-1 (Chk1) is an active transducer kinase at both the S and G2 checkpoints, rendering it a target for rational anticancer drug development. In the presence of DNA damage, Chk1 inactivation abrogates G2 arrest, resulting in preferential cancer cell death .This article serves to review the (1) current molecular pathways comprising the cell cycle checkpoint machinery, (2) inhibition of Chk1 as an effective means of abrogating G2 arrest, and (3) current Chk1 inhibitors in use in phase I clinical trials.

Zoledronic acid determines S-phase arrest but fails to induce apoptosis in cholangiocarcinoma cells

“…To date, however, the details of the molecular mechanism of cell cycle arrest involved remain obscure. The G1/S checkpoint is often compromised in many tumor cells due to mutation or deletion of tumor suppressor genes including pRb and TP53 [44]. Several studies conducted so far have assessed the deregulation of the pRb-pathway components in various human tumors and cell-lines, provided these pathway alterations play an obligatory role in tumorigenesis.…”

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

“…When damage is beyond repair, proteins in the DDR network mediate one of two effector functions: initiation of permanent cell cycle arrest (cellular senescence) or cell death (Zhou and Elledge, 2000;Abraham, 2001;Khanna and Jackson, 2001;Sancar et al, 2004). Characterizing these two outcomes will have important implications for understanding DDR signaling and improving the efficacy of DNA-damaging agents used in anticancer treatments (Zhou and Bartek, 2004;Bucher and Britten, 2008). Although Chk1 and Chk2 proteins exhibit comparable cellular activities, Chk1 is important for checkpoint and replication arms of the DDR signaling, whereas Chk2 is more important for DNA-damage-induced apoptosis (Zhou and Bartek, 2004).…”

“…Given that the majority of cancer cells are deficient in the G1/S DNA-damage checkpoint resulting in reliance on the S and G2 checkpoint for DNA repair and survival compared with normal cells with functioning G1 checkpoint, it is rational to inhibit these checkpoints to enhance the therapeutic index of current anticancer treatments. As the S-phase checkpoint acts to delay rather than arrest the cell cycle, cancer cells with damaged DNA may progress through this checkpoint only to halt at the G2 checkpoint, which is critical for the protection of the cancer cell genome (Bucher and Britten, 2008). The rationale of pharmacological checkpoint abrogation, specifically of the G2 checkpoint, in anticancer treatment has been a subject of numerous reviews (Tao and Lin, 2006;Bucher and Britten, 2008;Wang et al, 2009).…”

“…As the S-phase checkpoint acts to delay rather than arrest the cell cycle, cancer cells with damaged DNA may progress through this checkpoint only to halt at the G2 checkpoint, which is critical for the protection of the cancer cell genome (Bucher and Britten, 2008). The rationale of pharmacological checkpoint abrogation, specifically of the G2 checkpoint, in anticancer treatment has been a subject of numerous reviews (Tao and Lin, 2006;Bucher and Britten, 2008;Wang et al, 2009). Here, we will focus on the role of Chk1 kinase in the regulation of the G2 checkpoint with an emphasis on the outcomes that can be obtained from its abrogation.…”

“…Abrogation of the G2 checkpoint prevents cancer cells from repairing DNA damage, forcing them into the M phase prematurely (with damaged DNA) to produce subsequent antiproliferative effects (Morgan et al, 2005;Bucher and Britten, 2008). The Chk1 inhibitor PF-00477736 (Pfizer, New York, NY, USA) abrogates gemcitabine-induced S-phase arrest and allows cells to progress through the G2 checkpoint (Blasina et al, 2008).…”