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Targeting DNA Replication Stress for Cancer Therapy
The human cellular genome is under constant stress from extrinsic and intrinsic factors, which can lead to DNA damage and defective replication. In normal cells, DNA damage response (DDR) mediated by various checkpoints will either activate the DNA repair system or induce cellular apoptosis/senescen...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999839/ https://www.ncbi.nlm.nih.gov/pubmed/27548226 http://dx.doi.org/10.3390/genes7080051 |
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author | Zhang, Jun Dai, Qun Park, Dongkyoo Deng, Xingming |
author_facet | Zhang, Jun Dai, Qun Park, Dongkyoo Deng, Xingming |
author_sort | Zhang, Jun |
collection | PubMed |
description | The human cellular genome is under constant stress from extrinsic and intrinsic factors, which can lead to DNA damage and defective replication. In normal cells, DNA damage response (DDR) mediated by various checkpoints will either activate the DNA repair system or induce cellular apoptosis/senescence, therefore maintaining overall genomic integrity. Cancer cells, however, due to constitutive growth signaling and defective DDR, may exhibit “replication stress” —a phenomenon unique to cancer cells that is described as the perturbation of error-free DNA replication and slow-down of DNA synthesis. Although replication stress has been proven to induce genomic instability and tumorigenesis, recent studies have counterintuitively shown that enhancing replicative stress through further loosening of the remaining checkpoints in cancer cells to induce their catastrophic failure of proliferation may provide an alternative therapeutic approach. In this review, we discuss the rationale to enhance replicative stress in cancer cells, past approaches using traditional radiation and chemotherapy, and emerging approaches targeting the signaling cascades induced by DNA damage. We also summarize current clinical trials exploring these strategies and propose future research directions including the use of combination therapies, and the identification of potential new targets and biomarkers to track and predict treatment responses to targeting DNA replication stress. |
format | Online Article Text |
id | pubmed-4999839 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-49998392016-09-01 Targeting DNA Replication Stress for Cancer Therapy Zhang, Jun Dai, Qun Park, Dongkyoo Deng, Xingming Genes (Basel) Review The human cellular genome is under constant stress from extrinsic and intrinsic factors, which can lead to DNA damage and defective replication. In normal cells, DNA damage response (DDR) mediated by various checkpoints will either activate the DNA repair system or induce cellular apoptosis/senescence, therefore maintaining overall genomic integrity. Cancer cells, however, due to constitutive growth signaling and defective DDR, may exhibit “replication stress” —a phenomenon unique to cancer cells that is described as the perturbation of error-free DNA replication and slow-down of DNA synthesis. Although replication stress has been proven to induce genomic instability and tumorigenesis, recent studies have counterintuitively shown that enhancing replicative stress through further loosening of the remaining checkpoints in cancer cells to induce their catastrophic failure of proliferation may provide an alternative therapeutic approach. In this review, we discuss the rationale to enhance replicative stress in cancer cells, past approaches using traditional radiation and chemotherapy, and emerging approaches targeting the signaling cascades induced by DNA damage. We also summarize current clinical trials exploring these strategies and propose future research directions including the use of combination therapies, and the identification of potential new targets and biomarkers to track and predict treatment responses to targeting DNA replication stress. MDPI 2016-08-19 /pmc/articles/PMC4999839/ /pubmed/27548226 http://dx.doi.org/10.3390/genes7080051 Text en © 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Zhang, Jun Dai, Qun Park, Dongkyoo Deng, Xingming Targeting DNA Replication Stress for Cancer Therapy |
title | Targeting DNA Replication Stress for Cancer Therapy |
title_full | Targeting DNA Replication Stress for Cancer Therapy |
title_fullStr | Targeting DNA Replication Stress for Cancer Therapy |
title_full_unstemmed | Targeting DNA Replication Stress for Cancer Therapy |
title_short | Targeting DNA Replication Stress for Cancer Therapy |
title_sort | targeting dna replication stress for cancer therapy |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999839/ https://www.ncbi.nlm.nih.gov/pubmed/27548226 http://dx.doi.org/10.3390/genes7080051 |
work_keys_str_mv | AT zhangjun targetingdnareplicationstressforcancertherapy AT daiqun targetingdnareplicationstressforcancertherapy AT parkdongkyoo targetingdnareplicationstressforcancertherapy AT dengxingming targetingdnareplicationstressforcancertherapy |