CHEK again: Revisiting the development of CHK1 inhibitors for cancer therapy

McNeely, Samuel C.; Beckmann, Richard P.; Lin, Aimee K.

doi:10.1016/j.pharmthera.2013.10.005

Cited by 147 publications

(151 citation statements)

References 96 publications

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“…16 Chk1 is an essential kinase in governing cell cycle G 1 /S, S, and G 2 /M phase checkpoints and determining cellular responses to DNA damage. [22][23][24][25][26] In contrast to the well-known utility of Chk1 inhibitors in sensitizing tumors to chemotherapy agents, 23,27,28 Chk1 overexpression or downexpression also occurs in some types of tumors, including breast cancer, ovarian cancer, cervical cancer, and neuroblastoma. 22,[29][30][31][32][33] In our study, we found Chk1 mRNA and protein levels were upregulated in colorectal cancer tissues compared with paired normal tissues, and positively correlated with CCNB1 expression.…”

Section: Discussionmentioning

confidence: 99%

Chk1-induced CCNB1 overexpression promotes cell proliferation and tumor growth in human colorectal cancer

Fang

Liang

et al. 2014

Cancer Biology & Therapy

136

115

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Section: Discussionmentioning

confidence: 99%

Chk1-induced CCNB1 overexpression promotes cell proliferation and tumor growth in human colorectal cancer

Fang

Liang

et al. 2014

Cancer Biology & Therapy

136

115

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“…Cytosolic sequestration of CDC25B and CDC25C prevents the activation of CDK1 resulting in cell-cycle arrest at the G 2 -M boundary. A number of CHK1 inhibitors have been developed and entered the clinic as checkpoint inhibitors to increase the efficacy of chemotherapy in patients with p53-mutant cancer (7,8).…”

Section: Introductionmentioning

confidence: 99%

“…However, inhibition of CHK1 function also prevents localization of RAD51 to the invading repair strand during HRR, maintaining the accumulated breaks in the collapsed forks (16). Disaster continues to escalate for the CHK1 inhibited cell as the loss of the intra-S checkpoint permits the cell to continue up to the G 2 -M checkpoint with broken DNA (7). Ultimately, the cell enters mitosis with fragmented chromosomes resulting in cell death.…”

Section: Introductionmentioning

confidence: 99%

LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms

King

Diaz

McNeely

et al. 2015

Molecular Cancer Therapeutics

153

175

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CHK1 is a multifunctional protein kinase integral to both the cellular response to DNA damage and control of the number of active replication forks. CHK1 inhibitors are currently under investigation as chemopotentiating agents due to CHK1's role in establishing DNA damage checkpoints in the cell cycle. Here, we describe the characterization of a novel CHK1 inhibitor, LY2606368, which as a single agent causes double-stranded DNA breakage while simultaneously removing the protection of the DNA damage checkpoints. The action of LY2606368 is dependent upon inhibition of CHK1 and the corresponding increase in CDC25A activation of CDK2, which increases the number of replication forks while reducing their stability. Treatment of cells with LY2606368 results in the rapid appearance of TUNEL and pH2AX-positive double-stranded DNA breaks in the S-phase cell population. Loss of the CHK1-dependent DNA damage checkpoints permits cells with damaged DNA to proceed into early mitosis and die. The majority of treated mitotic nuclei consist of extensively fragmented chromosomes. Inhibition of apoptosis by the caspase inhibitor Z-VAD-FMK had no effect on chromosome fragmentation, indicating that LY2606368 causes replication catastrophe. Changes in the ratio of RPA2 to phosphorylated H2AX following LY2606368 treatment further support replication catastrophe as the mechanism of DNA damage. LY2606368 shows similar activity in xenograft tumor models, which results in significant tumor growth inhibition. LY2606368 is a potent representative of a novel class of drugs for the treatment of cancer that acts through replication catastrophe.

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“…34,35 Of the other changed genes in CPZ-treated mice, HUS1 and Chk1 encode components of cell cycle checkpoint complex able to cause cell cycle arrest in response to DNA repair and cell death thus preventing damaged cells from progressing through the cell cycle. [36][37][38] Ddit 3 (also referred to Gadd153, Chop) is a DNA damage-inducible transcript 3 protein. It is able to induce cell cycle arrest and plays an essential role in apoptosis and inflammation.…”

Section: Cuprizone Induced Cell Cycle Activationmentioning

confidence: 99%

Cyclin-dependent kinase inhibitor flavopiridol promotes remyelination in a cuprizone induced demyelination model

Mi¹,

Gao

Liu³

et al. 2016

Cell Cycle

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The cuprizone (CPZ) model has been widely used for the studies of de-and remyelination. The CPZexposed mice show oligodendrocyte precursor cells (OPCs) increase and mature oligodendrocytes decrease, suggesting an imbalance between proliferation and differentiation of OPCs. In the first experiment of this study, we examined the expression of cell cycle related genes in brains of mice following CPZ administration for 5 weeks by means of microarray assay. In addition, we performed a double labeling of BrdU and Ki-67 to calculate cell cycle exit index in the mice. Our results showed that CPZ administration up-regulated the expression of 16 cell cycle related genes, but down-regulated the expression of only one in the prefrontal cortex (PFC) of mice compared to control group. The treatment inhibited potential precursor cells exit from cell cycle. In the second experiment, we evaluated effects of a CDK inhibitor flavopiridol (FLA) on CPZ-induced neuropathological changes and spatial working memory impairment in mice.FLA treatment for one week effectively attenuated the CPZ-induced increases in NG2 positive cells, microglia and astrocytes, alleviated the concurrent mature oligodendrocyte loss and myelin breakdown, and improved spatial working memory deficit in the CPZ-exposed mice. These results suggest that CPZ-induced neuropathological changes involve in dysregulation of cell cycle related genes. The therapeutic effects of FLA on CPZ-exposed mice may be related to its ability of cell cycle inhibition.

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CHEK again: Revisiting the development of CHK1 inhibitors for cancer therapy

Cited by 147 publications

References 96 publications

Chk1-induced CCNB1 overexpression promotes cell proliferation and tumor growth in human colorectal cancer

Chk1-induced CCNB1 overexpression promotes cell proliferation and tumor growth in human colorectal cancer

LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms

Cyclin-dependent kinase inhibitor flavopiridol promotes remyelination in a cuprizone induced demyelination model

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