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Targeting DNA Damage Response as a Strategy to Treat HPV Infections

Mucosotropic human papillomaviruses (HPVs) cause prevalent anogenital infections, some of which can progress to cancers. It is imperative to identify efficacious drug candidates, as there are few therapeutic options. We have recapitulated a robust productive program of HPV-18 in organotypic raft cul...

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Autores principales: Banerjee, N. Sanjib, Moore, Dianne, Parker, Cameron J., Broker, Thomas R., Chow, Louise T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862220/
https://www.ncbi.nlm.nih.gov/pubmed/31683862
http://dx.doi.org/10.3390/ijms20215455
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author Banerjee, N. Sanjib
Moore, Dianne
Parker, Cameron J.
Broker, Thomas R.
Chow, Louise T.
author_facet Banerjee, N. Sanjib
Moore, Dianne
Parker, Cameron J.
Broker, Thomas R.
Chow, Louise T.
author_sort Banerjee, N. Sanjib
collection PubMed
description Mucosotropic human papillomaviruses (HPVs) cause prevalent anogenital infections, some of which can progress to cancers. It is imperative to identify efficacious drug candidates, as there are few therapeutic options. We have recapitulated a robust productive program of HPV-18 in organotypic raft cultures of primary human keratinocytes. The HPV E7 protein induces S phase reentry, along with DNA damage response (DDR) in differentiated cells to support viral DNA amplification. A number of small molecule inhibitors of DDR regulators are in clinical use or clinical trials to treat cancers. Here, we used our raft culture system to examine effects of inhibitors of ATR/Chk1 and ATM/Chk2 on HPV infection. The inhibitors impaired S-phase reentry and progression as well as HPV DNA amplification. The Chk1 inhibitor MK-8776 was most effective, reducing viral DNA amplification by 90–99% and caused DNA damage and apoptosis, preferentially in HPV infected cells. We found that this sensitivity was imparted by the E7 protein and report that MK-8776 also caused extensive cell death of cervical cancer cell lines. Furthermore, it sensitized the cells to cisplatin, commonly used to treat advanced cervical cancer. Based on these observations, the Chk1 inhibitors could be potential effective agents to be re-purposed to treat the spectrum of HPV infections in single or combination therapy.
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spelling pubmed-68622202019-12-05 Targeting DNA Damage Response as a Strategy to Treat HPV Infections Banerjee, N. Sanjib Moore, Dianne Parker, Cameron J. Broker, Thomas R. Chow, Louise T. Int J Mol Sci Article Mucosotropic human papillomaviruses (HPVs) cause prevalent anogenital infections, some of which can progress to cancers. It is imperative to identify efficacious drug candidates, as there are few therapeutic options. We have recapitulated a robust productive program of HPV-18 in organotypic raft cultures of primary human keratinocytes. The HPV E7 protein induces S phase reentry, along with DNA damage response (DDR) in differentiated cells to support viral DNA amplification. A number of small molecule inhibitors of DDR regulators are in clinical use or clinical trials to treat cancers. Here, we used our raft culture system to examine effects of inhibitors of ATR/Chk1 and ATM/Chk2 on HPV infection. The inhibitors impaired S-phase reentry and progression as well as HPV DNA amplification. The Chk1 inhibitor MK-8776 was most effective, reducing viral DNA amplification by 90–99% and caused DNA damage and apoptosis, preferentially in HPV infected cells. We found that this sensitivity was imparted by the E7 protein and report that MK-8776 also caused extensive cell death of cervical cancer cell lines. Furthermore, it sensitized the cells to cisplatin, commonly used to treat advanced cervical cancer. Based on these observations, the Chk1 inhibitors could be potential effective agents to be re-purposed to treat the spectrum of HPV infections in single or combination therapy. MDPI 2019-11-01 /pmc/articles/PMC6862220/ /pubmed/31683862 http://dx.doi.org/10.3390/ijms20215455 Text en © 2019 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 Article
Banerjee, N. Sanjib
Moore, Dianne
Parker, Cameron J.
Broker, Thomas R.
Chow, Louise T.
Targeting DNA Damage Response as a Strategy to Treat HPV Infections
title Targeting DNA Damage Response as a Strategy to Treat HPV Infections
title_full Targeting DNA Damage Response as a Strategy to Treat HPV Infections
title_fullStr Targeting DNA Damage Response as a Strategy to Treat HPV Infections
title_full_unstemmed Targeting DNA Damage Response as a Strategy to Treat HPV Infections
title_short Targeting DNA Damage Response as a Strategy to Treat HPV Infections
title_sort targeting dna damage response as a strategy to treat hpv infections
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862220/
https://www.ncbi.nlm.nih.gov/pubmed/31683862
http://dx.doi.org/10.3390/ijms20215455
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