Prevention of Radiation-Induced Salivary Gland Dysfunction Utilizing a CDK Inhibitor in a Mouse Model

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.

Botulinum Toxin Confers Radioprotection in Murine Salivary Glands

“…Therefore, we speculated that BTX pretreatment induces a dormant salivary state, which in turn could protect from radiation damage. Consistent with prior reports (10, 27), we detected a 50% decline in saliva flow within 3 days of radiation exposure. However, BTX-pretreated animals showed a reduction of only 25% in saliva flow rate compared with saline control.…”

Encapsulation of primary salivary gland cells in enzymatically degradable poly(ethylene glycol) hydrogels promotes acinar cell characteristics

“…Subsequently, chronic dry mouth syndrome (i.e., “xerostomia”) severely undermines oral health and function [1,2]. Though some radioprotective strategies are under development [3–8], current treatments for this major quality of life issue are only palliative [9]. Therefore, regenerative and/or radioprotective approaches for the salivary gland are critically needed.…”

Botulinum Toxin Confers Radioprotection in Murine Salivary Glands

“…Loss of acinar cells through apoptosis occurs during the acute phase. This process is p53 dependent and can be reversed by immunoglobulin F-1, CDK inhibition, or Wnt/β-catenin activation (6)(7)(8)(9)(10)(11). Alternatively, membrane lipid peroxidation is thought to induce damage to the secretory granules and acinar cellular lysis (12,13).…”