Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhang, Jun, Dai, Qun, Park, Dongkyoo, Deng, Xingming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2016
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
_version_ 1782450170984660992
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