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

• Published in: PloS one 2012-12, Vol.7 (12), p.e51363
• Main Authors: Martin, Katie L, Hill, Grace A, Klein, Rob R, Arnett, Deborah G, Burd, Randy, Limesand, Kirsten H
• Format: Article
• Language: English
• Subjects: Acinar cells; Analysis of Variance; Animal tissues; Animals; Apoptosis; Apoptosis - drug effects; Background radiation; Biology; Blotting, Western; Cancer; Cancer therapies; Cancer treatment; Caspase; Caspase 3; Cell cycle; Cyclin-dependent kinase; Cyclin-dependent kinases; Cyclin-Dependent Kinases - antagonists & inhibitors; Cytometry; Deoxyribonucleic acid; DNA; DNA Primers - genetics; DNA repair; DNA Repair - physiology; Enzyme inhibitors; Exocrine glands; Flow Cytometry; G2 Phase Cell Cycle Checkpoints - drug effects; Gene expression; Glands; Head & neck cancer; Head and neck cancer; Head and Neck Neoplasms - radiotherapy; Health aspects; Inhibitors; Insulin-like growth factor I; Interdisciplinary aspects; Ionizing radiation; Irradiation; Kinases; Medicine; Mice; Parotid gland; Physiology; Preservation; Proliferating Cell Nuclear Antigen; Purines - pharmacology; Purines - therapeutic use; Radiation; Radiation damage; Radiation effects; Radiation Injuries, Experimental - drug therapy; Radiation Injuries, Experimental - prevention & control; Radiation therapy; Radiotherapy - adverse effects; Real-Time Polymerase Chain Reaction; Roscovitine; Salivary gland; Salivary glands; Salivary Glands - cytology; Salivary Glands - drug effects; Salivary Glands - radiation effects; Side effects; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0051363

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. 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. 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.