TAT-mediated delivery of tousled protein to salivary glands protects against radiation-induced hypofunction

Gulshan Sunavala-Dossabhoy, Senthilnathan Palaniyandi, Charles Richardson, Arrigo De Benedetti, Lisa Schrott, Gloria Caldito

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Purpose: Patients treated with radiotherapy for head-and-neck cancer invariably suffer its deleterious side effect, xerostomia. Salivary hypofunction ensuing from the irreversible destruction of glands is the most common and debilitating oral complication affecting patients undergoing regional radiotherapy. Given that the current management of xerostomia is palliative and ineffective, efforts are now directed toward preventive measures to preserve gland function. The human homolog of Tousled protein, TLK1B, facilitates chromatin remodeling at DNA repair sites and improves cell survival against ionizing radiation (IR). Therefore, we wanted to determine whether a direct transfer of TLK1B protein to rat salivary glands could protect against IR-induced salivary hypofunction. Methods: The cell-permeable TAT-TLK1B fusion protein was generated. Rat acinar cell line and rat salivary glands were pretreated with TAT peptide or TAT-TLK1B before IR. The acinar cell survival in vitro and salivary function in vivo were assessed after radiation. Results: We demonstrated that rat acinar cells transduced with TAT-TLK1B were more resistant to radiation (D 0 = 4.13 ± 1.0 Gy; α/β = 0 Gy) compared with cells transduced with the TAT peptide (D 0 = 4.91 ± 1.0 Gy; α/β = 20.2 Gy). Correspondingly, retroductal instillation of TAT-TLK1B in rat submandibular glands better preserved salivary flow after IR (89%) compared with animals pretreated with Opti-MEM or TAT peptide (31% and 39%, respectively; p < 0.01). Conclusions: The results demonstrate that a direct transfer of TLK1B protein to the salivary glands effectively attenuates radiation-mediated gland dysfunction. Prophylactic TLK1B-protein therapy could benefit patients undergoing radiotherapy for head-and-neck cancer.

Original languageEnglish
Pages (from-to)257-265
Number of pages9
JournalInternational Journal of Radiation Oncology Biology Physics
Volume84
Issue number1
DOIs
StatePublished - Sep 1 2012

Keywords

  • Head and neck cancer
  • Radiotherapy
  • Salivary glands
  • TLK1
  • Tousled
  • Xerostomia

ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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