Characterization of novel Checkpoint kinase 1 inhibitors by in vitro assays and in human cancer cells treated with topoisomerase inhibitors

Ferry, Gilles; Studény, Aurélie; Bossard, Céline; Kubara, Philip M.; Zeyer, Denis; Renaud, Jean‐Paul; Casara, Patrick; Nanteuil, Guillaume De; Wierzbicki, Michel; Pfeiffer, Bruno; Prudhomme, Michelle; Léonce, Stéphane; Boutin, Jean A.; Golsteyn, Roy M.

doi:10.1016/j.lfs.2011.06.010

Cited by 11 publications

(8 citation statements)

References 52 publications

(68 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…By cisplatin treatment, WI-38 cells arrest largely in G1 and few cells expressed cyclin B1 protein, which would be critical for activation of Cdk1 and entry into mitosis. There are numerous genetic and experimental examples of how inhibition of Chk1 protein leads to entry into mitosis 45,46 or micronuclei formation. 42 It is noteworthy, however, that the simplest approach such as re-introducing functional p53 in a cancer cell line does not prevent mitotic catastrophe, or likely checkpoint adaptation.…”

Section: Micronuclei Cause Additional Damage To Dnamentioning

confidence: 99%

Cancer cells that survive checkpoint adaptation contain micronuclei that harbor damaged DNA

Lewis

Golsteyn

2016

Cell Cycle

Self Cite

View full text Add to dashboard Cite

We have examined the relationship between checkpoint adaptation (mitosis with damaged DNA) and micronuclei. Micronuclei in cancer cells are linked to genomic change, and may induce chromothripsis (chromosome shattering). We measured the cytotoxicity of the cancer drug cisplatin in M059K (glioma fibroblasts, IC50 15 mM). Nearly 100% of M059K cells were positive for histone gH2AX staining after 48 h treatment with a cytotoxic concentration of cisplatin. The proportion of micronucleated cells, as confirmed by microscopy using DAPI and lamin A/C staining, increased from 24% to 48%, and the total micronuclei in surviving cells accumulated over time. Promoting entry into mitosis with a checkpoint inhibitor increased the number of micronuclei in cells whereas blocking checkpoint adaptation with a Cdk inhibitor reduced the number of micronuclei. Interestingly, some micronuclei underwent asynchronous DNA replication, relative to the main nuclei, as measured by deoxy-bromo-uracil (BrdU) staining. These micronuclei stained positive for histone gH2AX, which was linked to DNA replication, suggesting that micronuclei arise from checkpoint adaptation and that micronuclei may continue to damage DNA. By contrast the normal cell line WI-38 did not undergo checkpoint adaptation when treated with cisplatin and did not show changes in micronuclei number. These data reveal that the production of micronuclei by checkpoint adaptation is part of a process that contributes to genomic change.

show abstract

Section: Micronuclei Cause Additional Damage To Dnamentioning

confidence: 99%

Cancer cells that survive checkpoint adaptation contain micronuclei that harbor damaged DNA

Lewis

Golsteyn

2016

Cell Cycle

Self Cite

View full text Add to dashboard Cite

show abstract

“…In these cases, cancer cells might enter mitosis more frequently than normal cells in response to DNA damage because they are more likely to be deficient in different aspects of cell cycle checkpoints [139], with 50% of human cancers containing a defective p53 gene [140,141]. Indeed, it has been shown that inhibiting the checkpoint kinases Chk1 and Chk2 can induce mitosis in treated human cancer cells [142–146]. …”

Section: Cell Cycle Checkpoints and Checkpoint Adaptationmentioning

confidence: 99%

Genotoxic Anti-Cancer Agents and Their Relationship to DNA Damage, Mitosis, and Checkpoint Adaptation in Proliferating Cancer Cells

Swift

Golsteyn

2014

IJMS

173

127

View full text Add to dashboard Cite

When a human cell detects damaged DNA, it initiates the DNA damage response (DDR) that permits it to repair the damage and avoid transmitting it to daughter cells. Despite this response, changes to the genome occur and some cells, such as proliferating cancer cells, are prone to genome instability. The cellular processes that lead to genomic changes after a genotoxic event are not well understood. Our research focuses on the relationship between genotoxic cancer drugs and checkpoint adaptation, which is the process of mitosis with damaged DNA. We examine the types of DNA damage induced by widely used cancer drugs and describe their effects upon proliferating cancer cells. There is evidence that cell death caused by genotoxic cancer drugs in some cases includes exiting a DNA damage cell cycle arrest and entry into mitosis. Furthermore, some cells are able to survive this process at a time when the genome is most susceptible to change or rearrangement. Checkpoint adaptation is poorly characterised in human cells; we predict that increasing our understanding of this pathway may help to understand genomic instability in cancer cells and provide insight into methods to improve the efficacy of current cancer therapies.

show abstract

“…Or else, the platform was involved in providing data on the biophysics of the interaction, most of the time, all steps of drug discovery contributed to the final results. Some findings have been published and showed the completeness of the approach that laid the foundations for the discovery and early clinical development of drug candidates [138,139,165].…”

Section: Discussionmentioning

confidence: 99%

“…Creating efficient collaborations with some groups, our first attempts were to characterize the interactions between some of our compounds and a given target in neurogenerative diseases [134][135][136]. We then embarked on several kinase-related projects that ended with the discovery of powerful compounds [137][138][139][140]. However, we needed more freedom to operate and establish proof of concept of the importance of these approaches to complement our drug discovery programs.…”

Section: Structuring: What Is the Hit/target Relationship At The Atommentioning

confidence: 99%

On the Organization of a Drug Discovery Platform

Nosjean¹,

Ferry²

2018

Drug Discovery - Concepts to Market

Self Cite

View full text Add to dashboard Cite

Some of the most exciting parts of work in the pharmaceutical industry are the steps leading up to drug discovery. This process can be oversimplified by describing it as a screening campaign involving the systematic testing of many compounds in a test relevant to a given pathology. This naïve description takes place without taking into consideration the numerous key steps that led up to the screening or the steps that might follow. The present chapter describes this whole process as it was conducted in our company during our early drug discovery activities. First, the purpose of the procedures is described and rationalized. Next follows a series of mostly published examples from our own work illustrating the various steps of the process from cloning to biophysics, including expression systems and membrane-bound protein purifications. We believe that what is described here presents an example of how pharmaceutical industry research can organize its platform(s) when the goal is to find and qualify a new preclinical drug candidate using cutting-edge technologies and a lot of hard work.

show abstract

Characterization of novel Checkpoint kinase 1 inhibitors by in vitro assays and in human cancer cells treated with topoisomerase inhibitors

Cited by 11 publications

References 52 publications

Cancer cells that survive checkpoint adaptation contain micronuclei that harbor damaged DNA

Cancer cells that survive checkpoint adaptation contain micronuclei that harbor damaged DNA

Genotoxic Anti-Cancer Agents and Their Relationship to DNA Damage, Mitosis, and Checkpoint Adaptation in Proliferating Cancer Cells

On the Organization of a Drug Discovery Platform

Contact Info

Product

Resources

About