Prevention of radiation-induced salivary gland dysfunction utilizing a CDK inhibitor in a mouse model.

<h4>Background</h4>Treatment of head and neck cancer with radiation often results in damage to surrounding normal tissues such as salivary glands. Permanent loss of function in the salivary glands often leads patients to discontinue treatment due to incapacitating side effects. It has pr...

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Autores principales:	Katie L Martin, Grace A Hill, Rob R Klein, Deborah G Arnett, Randy Burd, Kirsten H Limesand
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/43e615c81dfa4af9a15f2c9251404a6e
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spelling	oai:doaj.org-article:43e615c81dfa4af9a15f2c9251404a6e2021-11-18T08:05:56ZPrevention of radiation-induced salivary gland dysfunction utilizing a CDK inhibitor in a mouse model.1932-620310.1371/journal.pone.0051363https://doaj.org/article/43e615c81dfa4af9a15f2c9251404a6e2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23236487/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Treatment of head and neck cancer with radiation often results in damage to surrounding normal tissues such as salivary glands. Permanent loss of function in the salivary glands often leads patients to discontinue treatment due to incapacitating side effects. It has previously been shown that IGF-1 suppresses radiation-induced apoptosis and enhances G2/M arrest leading to preservation of salivary gland function. In an effort to recapitulate the effects of IGF-1, as well as increase the likelihood of translating these findings to the clinic, the small molecule therapeutic Roscovitine, is being tested. Roscovitine is a cyclin-dependent kinase inhibitor that acts to transiently inhibit cell cycle progression and allow for DNA repair in damaged tissues.<h4>Methodology/principal findings</h4>Treatment with Roscovitine prior to irradiation induced a significant increase in the percentage of cells in the G(2)/M phase, as demonstrated by flow cytometry. In contrast, mice treated with radiation exhibit no differences in the percentage of cells in G(2)/M when compared to unirradiated controls. Similar to previous studies utilizing IGF-1, pretreatment with Roscovitine leads to a significant up-regulation of p21 expression and a significant decrease in the number of PCNA positive cells. Radiation treatment leads to a significant increase in activated caspase-3 positive salivary acinar cells, which is suppressed by pretreatment with Roscovitine. Administration of Roscovitine prior to targeted head and neck irradiation preserves normal tissue function in mouse parotid salivary glands, both acutely and chronically, as measured by salivary output.<h4>Conclusions/significance</h4>These studies suggest that induction of transient G(2)/M cell cycle arrest by Roscovitine allows for suppression of apoptosis, thus preserving normal salivary function following targeted head and neck irradiation. This could have an important clinical impact by preventing the negative side effects of radiation therapy in surrounding normal tissues.Katie L MartinGrace A HillRob R KleinDeborah G ArnettRandy BurdKirsten H LimesandPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 12, p e51363 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Katie L Martin Grace A Hill Rob R Klein Deborah G Arnett Randy Burd Kirsten H Limesand Prevention of radiation-induced salivary gland dysfunction utilizing a CDK inhibitor in a mouse model.
description	<h4>Background</h4>Treatment of head and neck cancer with radiation often results in damage to surrounding normal tissues such as salivary glands. Permanent loss of function in the salivary glands often leads patients to discontinue treatment due to incapacitating side effects. It has previously been shown that IGF-1 suppresses radiation-induced apoptosis and enhances G2/M arrest leading to preservation of salivary gland function. In an effort to recapitulate the effects of IGF-1, as well as increase the likelihood of translating these findings to the clinic, the small molecule therapeutic Roscovitine, is being tested. Roscovitine is a cyclin-dependent kinase inhibitor that acts to transiently inhibit cell cycle progression and allow for DNA repair in damaged tissues.<h4>Methodology/principal findings</h4>Treatment with Roscovitine prior to irradiation induced a significant increase in the percentage of cells in the G(2)/M phase, as demonstrated by flow cytometry. In contrast, mice treated with radiation exhibit no differences in the percentage of cells in G(2)/M when compared to unirradiated controls. Similar to previous studies utilizing IGF-1, pretreatment with Roscovitine leads to a significant up-regulation of p21 expression and a significant decrease in the number of PCNA positive cells. Radiation treatment leads to a significant increase in activated caspase-3 positive salivary acinar cells, which is suppressed by pretreatment with Roscovitine. Administration of Roscovitine prior to targeted head and neck irradiation preserves normal tissue function in mouse parotid salivary glands, both acutely and chronically, as measured by salivary output.<h4>Conclusions/significance</h4>These studies suggest that induction of transient G(2)/M cell cycle arrest by Roscovitine allows for suppression of apoptosis, thus preserving normal salivary function following targeted head and neck irradiation. This could have an important clinical impact by preventing the negative side effects of radiation therapy in surrounding normal tissues.
format	article
author	Katie L Martin Grace A Hill Rob R Klein Deborah G Arnett Randy Burd Kirsten H Limesand
author_facet	Katie L Martin Grace A Hill Rob R Klein Deborah G Arnett Randy Burd Kirsten H Limesand
author_sort	Katie L Martin
title	Prevention of radiation-induced salivary gland dysfunction utilizing a CDK inhibitor in a mouse model.
title_short	Prevention of radiation-induced salivary gland dysfunction utilizing a CDK inhibitor in a mouse model.
title_full	Prevention of radiation-induced salivary gland dysfunction utilizing a CDK inhibitor in a mouse model.
title_fullStr	Prevention of radiation-induced salivary gland dysfunction utilizing a CDK inhibitor in a mouse model.
title_full_unstemmed	Prevention of radiation-induced salivary gland dysfunction utilizing a CDK inhibitor in a mouse model.
title_sort	prevention of radiation-induced salivary gland dysfunction utilizing a cdk inhibitor in a mouse model.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/43e615c81dfa4af9a15f2c9251404a6e
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Prevention of radiation-induced salivary gland dysfunction utilizing a CDK inhibitor in a mouse model.

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