Abstract
BackgroundTreatment 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.Methodology/Principal FindingsTreatment with Roscovitine prior to irradiation induced a significant increase in the percentage of cells in the G2/M phase, as demonstrated by flow cytometry. In contrast, mice treated with radiation exhibit no differences in the percentage of cells in G2/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.Conclusions/SignificanceThese studies suggest that induction of transient G2/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.
Highlights
It is estimated that over 40,000 cases of head and neck cancer will be diagnosed in the United States in 2012 [1]
Patients undergoing radiotherapy for treatment of head and neck cancer often suffer from debilitating side effects related to radiation-induced damage of the salivary glands and loss of stimulated salivary flow
In this study we focused on the use of Roscovitine, a cyclindependent kinase inhibitor, as a possible preventative therapy for salivary gland dysfunction
Summary
It is estimated that over 40,000 cases of head and neck cancer will be diagnosed in the United States in 2012 [1]. Head and neck cancer is the 6th most common in the world, having a higher incidence in developing countries [2]. These cancers are often associated with increased tobacco and alcohol use [2]. Irradiation of the head and neck region often exposes surrounding non-diseased tissues to incidental radiation, resulting in secondary side effects. Intensity-modulated radiation therapy (IMRT) is a type of radiotherapy used to spare normal tissues, like the salivary glands, in order to reduce the secondary side effects [3]. Treatment of head and neck cancer with radiation often results in damage to surrounding normal tissues such as salivary glands. Roscovitine is a cyclin-dependent kinase inhibitor that acts to transiently inhibit cell cycle progression and allow for DNA repair in damaged tissues
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