339 POSTER Identification of XL413, a selective Cdc7 kinase inhibitor which induces cell cycle arrest and exhibits potent antitumor activity

2008 ◽  
Vol 6 (12) ◽  
pp. 108 ◽  
Author(s):  
S. Robertson
Keyword(s):  
Cell Cycle ◽  
Antitumor Activity ◽  
Cell Cycle Arrest ◽  
Kinase Inhibitor ◽  
Cycle Arrest ◽  
Cdc7 Kinase

scholarly journals Mitogen-Activated Protein Kinase Hog1 Mediates Adaptation to G1 Checkpoint Arrest during Arsenite and Hyperosmotic Stress

2008 ◽  
Vol 7 (8) ◽  
pp. 1309-1317 ◽  
Author(s):  
Iwona Migdal ◽  
Yulia Ilina ◽  
Markus J. Tamás ◽  
Robert Wysocki
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Cell Cycle Arrest ◽  
Kinase Inhibitor ◽  
Hyperosmotic Stress ◽  
Mitogen Activated Protein Kinase ◽  
Hog Pathway ◽  
Cycle Arrest ◽  
Mitogen Activated Protein

ABSTRACT Cells slow down cell cycle progression in order to adapt to unfavorable stress conditions. Yeast (Saccharomyces cerevisiae) responds to osmotic stress by triggering G1 and G2 checkpoint delays that are dependent on the mitogen-activated protein kinase (MAPK) Hog1. The high-osmolarity glycerol (HOG) pathway is also activated by arsenite, and the hog1Δ mutant is highly sensitive to arsenite, partly due to increased arsenite influx into hog1Δ cells. Yeast cell cycle regulation in response to arsenite and the role of Hog1 in this process have not yet been analyzed. Here, we found that long-term exposure to arsenite led to transient G1 and G2 delays in wild-type cells, whereas cells that lack the HOG1 gene or are defective in Hog1 kinase activity displayed persistent G1 cell cycle arrest. Elevated levels of intracellular arsenite and “cross talk” between the HOG and pheromone response pathways, observed in arsenite-treated hog1Δ cells, prolonged the G1 delay but did not cause a persistent G1 arrest. In contrast, deletion of the SIC1 gene encoding a cyclin-dependent kinase inhibitor fully suppressed the observed block of G1 exit in hog1Δ cells. Moreover, the Sic1 protein was stabilized in arsenite-treated hog1Δ cells. Interestingly, Sic1-dependent persistent G1 arrest was also observed in hog1Δ cells during hyperosmotic stress. Taken together, our data point to an important role of the Hog1 kinase in adaptation to stress-induced G1 cell cycle arrest.

scholarly journals Delivery of a TNF‐α–derived peptide by nanoparticles enhances its antitumor activity by inducing cell‐cycle arrest and caspase‐dependent apoptosis

2018 ◽  
Vol 32 (12) ◽  
pp. 6948-6964 ◽  
Author(s):  
Qiuxia Yan ◽  
Xueming Chen ◽  
Huizhen Gong ◽  
Pei Qiu ◽  
Xing Xiao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Antitumor Activity ◽  
Cell Cycle Arrest ◽  
Cycle Arrest ◽  
Tnf Α

scholarly journals Differential activation of target cellular promoters by p53 mutants with impaired apoptotic function.

1996 ◽  
Vol 16 (9) ◽  
pp. 4952-4960 ◽  
Author(s):  
R L Ludwig ◽  
S Bates ◽  
K H Vousden
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Dna Sequences ◽  
Transcriptional Activation ◽  
Cellular Response ◽  
Kinase Inhibitor ◽  
Cell Types ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Cycle Arrest ◽  
P53 Tumor Suppressor Protein

The p53 tumor suppressor protein is a sequence-specific transcriptional activator, a function which contributes to cell cycle arrest and apoptosis induced by p53 in appropriate cell types. Analysis of a series of p53 point mutants has revealed the potential for selective loss of the ability to transactivate some, but not all, cellular p53-responsive promoters. p53 175P and p53 181L are tumor-derived p53 point mutants which were previously characterized as transcriptionally active. Both mutants retained the ability to activate expression of the cyclin-dependent kinase inhibitor p2lcip1/waf1, and this activity correlated with the ability to induce a G1 cell cycle arrest. However, an extension of this survey to include other p53 targets showed that p53 175P was defective in the activation of p53-responsive sequences derived from the bax promoter and the insulin-like growth factor-binding protein 3 gene (IGF-BP3) promoter, while p53 181L showed loss of the ability to activate a promoter containing IGF-BP3 box B sequences. Failure to activate transcription was also reflected in the reduced ability of the mutants to bind the p53-responsive DNA sequences present in these promoters. These specific defects in transcriptional activation correlated with the impaired apoptotic function displayed by these mutants, and the results suggest that activation of cell cycle arrest genes by p53 can be separated from activation of genes with a role in mediating the p53 apoptotic response. The cellular response to p53 activation may therefore depend, at least in part, on which group of p53-responsive genes become transcriptionally activated.

Cdc7 inhibition as a novel approach for pancreas cancer therapy.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15059-e15059
Author(s):  
Mark G. Frattini ◽  
Lucia Regales ◽  
Ruth Santos ◽  
Diana Carrillo
Keyword(s):  
Cell Cycle ◽  
Pancreatic Cancer ◽  
Dna Damage ◽  
Cell Viability ◽  
Cell Cycle Arrest ◽  
Western Blotting ◽  
Kinase Activity ◽  
S Phase ◽  
Cycle Arrest ◽  
Cdc7 Kinase

e15059 Background: Pancreatic cancer is the fourth leading cause of cancer death in the USA. In 2012, 43,920 people will be diagnosed and 37,390 people will die of this disease. 95% of tumors reveal loss of the p16 protein, a regulator of the G1 to S phase transition. Cdc7 is a conserved kinase required for the initiation of DNA replication, is a target of the S-phase checkpoint, and has a role in controlling the DNA damage response. Downregulation of Cdc7 kinase activity resulted in slowing of S-phase and cell cycle arrest followed by accumulation of DNA damage. Cdc7 has been shown to be over-expressed in many different tumors including the majority of solid and liquid tumors. In our laboratory a novel natural product small molecule inhibitor (MSK-777) has been identified, developed and shown to be efficacious in cell based cytotoxicity assays and multiple animal models of cancer. Methods: We have examined the efficacy of Cdc7 kinase inhibition as a therapeutic approach for pancreatic cancer by examining the sensitivity of MSK-777 in Capan-1, BxPC3, and PANC-1 cell lines. These cells were treated with MSK-777, control (DMSO), or hydroxyurea and collected for viable cell counts, fluorescence-activated cell sorting (FACS), and western blotting. Results: Cell viability analyses revealed that MSK-777 had a dramatic effect after 24 hours, reducing cell viability to less then 20% in BxPC3 cells. FACS results demonstrated that MSK-777 exposure resulted in cell cycle arrest at G1/S in Capan-1 and PANC-1 cells by 48 hours while BxPC3 cells showed a significant sub-G1 population by 24 hours, indicating apoptotic cell death. Western blotting showed that in BxPC3 cells phosphorylation of the mini-chromosome maintenance 2 protein (Mcm2) disappeared by 24 hours, indicating inactivation of the helicase that unwinds the strands of DNA during replication. Western blots of Capan-1 and PANC-1 cells showed lower levels of phosphorylated Mcm2 by 48 hours. Conclusions: We are currently examining the efficacy of MSK-777 in mouse models of orthotopically injected pancreatic cancer cells. Based on these collective results, inhibition of Cdc7 kinase activity with MSK-777 represents a novel and promising therapy for this deadly disease.

scholarly journals Inactivation of p21 by E1A Leads to the Induction of Apoptosis in DNA-Damaged Cells

2001 ◽  
Vol 75 (20) ◽  
pp. 9844-9856 ◽  
Author(s):  
Debasis Chattopadhyay ◽  
Mrinal K. Ghosh ◽  
Asoke Mal ◽  
Marian L. Harter
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Anticancer Agents ◽  
Kinase Inhibitor ◽  
Human Colon ◽  
Wild Type ◽  
Human Colon Carcinoma Cell ◽  
Adenovirus E1a ◽  
Cycle Arrest ◽  
Induction Of Apoptosis

ABSTRACT A major impediment to successful chemotherapy is the propensity for some tumor cells to undergo cell cycle arrest rather than apoptosis. It is well established, however, that the adenovirus E1A protein can sensitize these cells to the induction of apoptosis by anticancer agents. To further understand how E1A enhances chemosensitivity, we have made use of a human colon carcinoma cell line (HCT116) which typically undergoes cell cycle arrest in response to chemotherapeutic drugs. As seen by the analysis of E1A mutants, we show here that E1A can induce apoptosis in these cells by neutralizing the activities of the cyclin-dependent kinase inhibitor p21. E1A's ability to interact with p21 and thereby restore Cdk2 activity in DNA-damaged cells correlates with the reversal of G1 arrest, which in turn leads to apoptosis. Analysis of E1A mutants failing to bind p300 (also called CBP) or Rb shows that they are almost identical to wild-type E1A in their ability to initially overcome a G1 arrest in cells after DNA damage, while an E1A mutant failing to bind p21 is not. However, over time, this mutant, which can still target Rb, is far more efficient in accumulating cells with a DNA content greater than 4N but is similar to wild-type E1A and the other E1A mutants in releasing cells from a p53-mediated G2 block following chemotherapeutic treatment. Thus, we suggest that although E1A requires the binding of p21 to create an optimum environment for apoptosis to occur in DNA-damaged cells, E1A's involvement in other pathways may be contributing to this process as well. A model is proposed to explain the implications of these findings.

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