Inhibiting DNA-PKCS radiosensitizes human osteosarcoma cells

Tewodros Mamo, Ann C. Mladek, Kris L. Shogren, Carl Gustafson, Shiv K. Gupta, Scott M. Riester, Avudaiappan Maran, Mario Galindo, Andre J van Wijnen, Jann N Sarkaria, Michael J Yaszemski

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Osteosarcoma survival rate has not improved over the past three decades, and the debilitating side effects of the surgical treatment suggest the need for alternative local control approaches. Radiotherapy is largely ineffective in osteosarcoma, indicating a potential role for radiosensitizers. Blocking DNA repair, particularly by inhibiting the catalytic subunit of DNA-dependent protein kinase (DNA-PKCS), is an attractive option for the radiosensitization of osteosarcoma. In this study, the expression of DNA-PKCS in osteosarcoma tissue specimens and cell lines was examined. Moreover, the small molecule DNA-PKCS inhibitor, KU60648, was investigated as a radiosensitizing strategy for osteosarcoma cells in vitro. DNA-PKCS was consistently expressed in the osteosarcoma tissue specimens and cell lines studied. Additionally, KU60648 effectively sensitized two of those osteosarcoma cell lines (143B cells by 1.5-fold and U2OS cells by 2.5-fold). KU60648 co-treatment also altered cell cycle distribution and enhanced DNA damage. Cell accumulation at the G2/M transition point increased by 55% and 45%, while the percentage of cells with >20 γH2AX foci were enhanced by 59% and 107% for 143B and U2OS cells, respectively. These results indicate that the DNA-PKCS inhibitor, KU60648, is a promising radiosensitizing agent for osteosarcoma.

Original languageEnglish (US)
Pages (from-to)307-313
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume486
Issue number2
DOIs
StatePublished - Apr 29 2017

Keywords

  • DNA-PK
  • DNA-PKcs
  • KU60648
  • Osteosarcoma
  • Radiosensitizers
  • Radiotherapy

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Mamo, T., Mladek, A. C., Shogren, K. L., Gustafson, C., Gupta, S. K., Riester, S. M., Maran, A., Galindo, M., van Wijnen, A. J., Sarkaria, J. N., & Yaszemski, M. J. (2017). Inhibiting DNA-PKCS radiosensitizes human osteosarcoma cells. Biochemical and Biophysical Research Communications, 486(2), 307-313. https://doi.org/10.1016/j.bbrc.2017.03.033