Inhibition of NF-κB and DNA double-strand break repair by DMAPT sensitizes non-small-cell lung cancers to X-rays

Neil C. Estabrook, Helen Chin-Sinex, Anthony J. Borgmann, Ryan M. Dhaemers, Ronald H. Shapiro, David Gilley, Nazmul Huda, Peter Crooks, Christopher Sweeney, Marc S. Mendonca

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

We investigated the efficacy and mechanism of dimethylaminoparthenolide (DMAPT), an NF-κB inhibitor, to sensitize human lung cancer cells to X-ray killing in vitro and in vivo. We tested whether DMAPT increased the effectiveness of single and fractionated X-ray treatment through inhibition of NF-κB and/or DNA double-strand break (DSB) repair. Treatment with DMAPT decreased plating efficiency, inhibited constitutive and radiation-induced NF-κB binding activity, and enhanced radiation-induced cell killing by dose modification factors of 1.8 and 1.4 in vitro. X-ray fractionation demonstrated that DMAPT inhibited split-dose recovery/repair, and neutral DNA comet assays confirmed that DMAPT altered the fast and slow components of X-ray-induced DNA DSB repair. Knockdown of the NF-κB family member p65 by siRNA increased radiation sensitivity and completely inhibited split-dose recovery in a manner very similar to DMAPT treatment. The data suggest a link between inhibition of NF-κB and inhibition of DSB repair by DMAPT that leads to enhancement of X-ray-induced cell killing in vitro in non-small-cell lung cancer cells. Studies of A549 tumor xenografts in nude mice demonstrated that DMAPT enhanced X-ray-induced tumor growth delay in vivo.

Original languageEnglish (US)
Pages (from-to)2249-2258
Number of pages10
JournalFree Radical Biology and Medicine
Volume51
Issue number12
DOIs
StatePublished - Dec 15 2011

Keywords

  • A549
  • DMAPT
  • Double-strand DNA break repair
  • Free radicals
  • H1299
  • NF-κB
  • X-rays

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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  • Cite this

    Estabrook, N. C., Chin-Sinex, H., Borgmann, A. J., Dhaemers, R. M., Shapiro, R. H., Gilley, D., Huda, N., Crooks, P., Sweeney, C., & Mendonca, M. S. (2011). Inhibition of NF-κB and DNA double-strand break repair by DMAPT sensitizes non-small-cell lung cancers to X-rays. Free Radical Biology and Medicine, 51(12), 2249-2258. https://doi.org/10.1016/j.freeradbiomed.2011.09.029