title: The Rapalogue, CCI-779, improves salivary gland function following radiation.
abstract: The standard of care for head and neck cancer typically includes surgical resection of the tumor followed by targeted head and neck radiation. However depending on tumor location and stage, some cases may not require surgical resection while others may be treated with chemoradiation. Unfortunately, these radiation treatments cause chronic negative side effects for patients. These side effects are associated with damage to surrounding normal salivary gland tissue and include xerostomia, changes in taste and malnutrition. The underlying mechanisms of chronic radiation-induced salivary gland dysfunction are unknown, however, in rodent models persistently elevated proliferation is correlated with reduced stimulated salivary flow. The rapalogue, CCI-779, has been used in other cell systems to induce autophagy and reduce proliferation, therefore the aim of this study was to determine if CCI-779 could be utilized to ameliorate chronic radiation-induced salivary gland dysfunction. Four to six week old Atg5f/f; Aqp5-Cre, Atg5+/+; Aqp5-Cre and FVB mice were treated with targeted head and neck radiation. FVB mice were treated with CCI-779, chloroquine, or DMSO post-radiation. Stimulated salivary flow rates were determined and parotid and submandibular salivary gland tissues were collected for analyses. Mice with a defect in autophagy, via a conditional knockout of Atg5 in the salivary glands, display increased compensatory proliferation in the acinar cell compartment and hypertrophy at 24-72 hours following radiation. FVB mice treated with post-therapy CCI-779 have significant improvements in salivary gland physiology as determined by stimulated salivary flow rates, proliferation indices and amylase production and secretion. Consequently, post-radiation use of CCI-779 allows for improvement of salivary gland function and reestablishment of glandular homeostasis. As CCI-779 is already FDA approved for other uses, it could have a secondary use to alleviate the chronic side effects in head and neck cancer patients who have completed anti-tumor therapy.
authors.affiliation: Department of Nutritional Sciences, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Maria
authors.initials: M
authors.lastname: Morgan-Bathke
authors.affiliation: Department of Nutritional Sciences, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Zoey I
authors.initials: ZI
authors.lastname: Harris
authors.affiliation: Department of Nutritional Sciences, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Deborah G
authors.initials: DG
authors.lastname: Arnett
authors.affiliation: Department of Pathology, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Rob R
authors.initials: RR
authors.lastname: Klein
authors.affiliation: Department of Nutritional Sciences, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Randy
authors.initials: R
authors.lastname: Burd
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, California, United States of America.
authors.forename: David K
authors.initials: DK
authors.lastname: Ann
authors.affiliation: Department of Nutritional Sciences, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Kirsten H
authors.initials: KH
authors.lastname: Limesand
mesh_terms: D000681:Amylases / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000528:radiation effects; D000071187:Autophagy-Related Protein 5; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D006258:Head and Neck Neoplasms / Q000532:radiotherapy; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010306:Parotid Gland / Q000166:cytology / Q000187:drug effects* / Q000502:physiology* / Q000528:radiation effects; D020127:Recovery of Function / Q000187:drug effects* / Q000528:radiation effects*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D013363:Submandibular Gland / Q000166:cytology / Q000187:drug effects* / Q000502:physiology* / Q000528:radiation effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; C401859:temsirolimus; D058570:TOR Serine-Threonine Kinases; D000681:Amylases; D020123:Sirolimus