The rapalogue, CCI-779, improves salivary gland function following radiation

Maria Morgan-Bathke, Zoey I. Harris, Deborah G. Arnett, Rob R. Klein, Randy M Burd, David K. Ann, Kirsten Limesand

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 antitumor therapy.

Original languageEnglish (US)
Article numbere113183
JournalPLoS One
Volume9
Issue number12
DOIs
StatePublished - Dec 1 2014

Fingerprint

salivary glands
Salivary Glands
Radiation
autophagy
adverse effects
mice
resection
Autophagy
neck
Head and Neck Neoplasms
Tumors
Neck
Head
Flow rate
chloroquine
acinar cells
therapeutics
Tissue
neoplasms
Xerostomia

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

The rapalogue, CCI-779, improves salivary gland function following radiation. / Morgan-Bathke, Maria; Harris, Zoey I.; Arnett, Deborah G.; Klein, Rob R.; Burd, Randy M; Ann, David K.; Limesand, Kirsten.

In: PLoS One, Vol. 9, No. 12, e113183, 01.12.2014.

Research output: Contribution to journalArticle

Morgan-Bathke M, Harris ZI, Arnett DG, Klein RR, Burd RM, Ann DK et al. The rapalogue, CCI-779, improves salivary gland function following radiation. PLoS One. 2014 Dec 1;9(12). e113183. https://doi.org/10.1371/journal.pone.0113183
Morgan-Bathke, Maria ; Harris, Zoey I. ; Arnett, Deborah G. ; Klein, Rob R. ; Burd, Randy M ; Ann, David K. ; Limesand, Kirsten. / The rapalogue, CCI-779, improves salivary gland function following radiation. In: PLoS One. 2014 ; Vol. 9, No. 12.
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