Pharmacological Abrogation of S-Phase Checkpoint Enhances the Anti-Tumor Activity of Gemcitabine In Vivo

Matthews, David J.; Yakes, F. Michael; Chen, Jason; Tadano, Michele; Bornheim, Lester M.; Clary, Douglas O.; Tai, Albert; Wagner, Jill M.; Miller, Nicole; Kim, Yong D.; Robertson, Scott; Murray, Louis; Karnitz, Larry M.

doi:10.4161/cc.6.1.3699

Cited by 122 publications

(97 citation statements)

References 36 publications

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“…31 In cells treated with gemcitabine, Chk1 inhibition abolishes S-phase checkpoint 27,32 and causes premature mitosis. 26,27,33,34 However, a previous study indicated a lack of correlation between premature mitotic entry and cytotoxicity 35 bringing into question the mechanism for chemosensitization by Chk1 inhibitors. cells treated with gemcitabine and AZD7762 was likely due to reduced total Chk1 protein.…”

Section: Resultsmentioning

confidence: 99%

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Chk1 inhibition after replicative stress activates a double strand break response mediated by ATM and DNA-dependent protein kinase

McNeely

Conti²,

Sheikh³

et al. 2010

Cell Cycle

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Section: Resultsmentioning

confidence: 99%

“…32,33 The kinase mediating the increase in γH2AX and how it relates to the effect of Chk1 inhibition on stalled replication forks have not been elucidated.…”

Section: Chk1 Inhibition After Replicative Stress Activates a Double mentioning

confidence: 99%

Chk1 inhibition after replicative stress activates a double strand break response mediated by ATM and DNA-dependent protein kinase

McNeely

Conti²,

Sheikh³

et al. 2010

Cell Cycle

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show abstract

“…In a CML nude mice survival model, the combination of XL844 and daunorubicin caused a significant increase in median survival time. In a panel of multiple solid tumour cell lines, XL844 had little effect as a single agent, but substantially increased the cytotoxicity of gemcitabine (Matthews et al, 2007). XL844 was shown to affect both the S and G2 checkpoints by blocking gemcitabine-induced DSBs and CDC25A phosphorylation, inducing premature mitotic entry.…”

Section: Xl844mentioning

confidence: 99%

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

2008

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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.

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“…For example, nucleoside analog exposure causes the phosphorylation of the DNA damage responsive histone, H2AX, which forms nuclear foci at sites of stalled replication forks (Figure 3). Upon checkpoint abrogation of gemcitabine-induced S phase arrested cells by inhibition of Chk1, H2AX phosphorylation further increases by 10-fold and is associated with a decrease in clonogenic survival (Matthews et al, 2007;Ewald et al, 2007), thus suggesting lethal increases in DNA damage. A similar effect was observed after only a 2-h exposure to gemcitabine.…”

Section: Checkpoint Dysregulationmentioning

confidence: 99%

“…In experimental systems, pharmacological inhibition of Chk1 in nucleoside analog-arrested cells results in rapid abrogation of the checkpoint, enhanced DNA damage and increased apoptosis Liu et al, 2005;Xiao et al, 2005;Matthews et al, 2007;Ewald et al, 2007).…”

Section: Checkpoint Dysregulationmentioning

confidence: 99%

Nucleoside analogs: molecular mechanisms signaling cell death

2008

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Nucleoside analogs are structurally similar antimetabolites that have a broad range of action and are clinically active in both solid tumors and hematological malignancies. Many of these agents are incorporated into DNA by polymerases during normal DNA synthesis, an action that blocks further extension of the nascent strand and causes stalling of replication forks. The molecular mechanisms that sense stalled replication forks activate cell cycle checkpoints and DNA repair processes, which may contribute to drug resistance. When replication forks are not stabilized by these molecules or when subsequent DNA repair processes are overwhelmed, apoptosis is initiated either by these same DNA damage sensors or by alternative mechanisms. Recently, strategies aimed at targeting DNA damage checkpoints or DNA repair processes have demonstrated effectiveness in sensitizing cells to nucleoside analogs, thus offering a means to elude drug resistance. In addition to their DNA synthesisdirected actions many nucleoside analogs trigger apoptosis by unique mechanisms, such as causing epigenetic modifications or by direct activation of the apoptosome. A review of the cellular and molecular responses to clinically relevant agents provides an understanding of the mechanisms that cause apoptosis and may provide rationale for the development of novel therapeutic strategies.

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Pharmacological Abrogation of S-Phase Checkpoint Enhances the Anti-Tumor Activity of Gemcitabine In Vivo

Cited by 122 publications

References 36 publications

Chk1 inhibition after replicative stress activates a double strand break response mediated by ATM and DNA-dependent protein kinase

Chk1 inhibition after replicative stress activates a double strand break response mediated by ATM and DNA-dependent protein kinase

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

Nucleoside analogs: molecular mechanisms signaling cell death

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