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 Mendonca

Research output: Contribution to journalArticle

17 Citations (Scopus)

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

Fingerprint

Double-Stranded DNA Breaks
Non-Small Cell Lung Carcinoma
Repair
Cells
X-Rays
X rays
DNA
Dosimetry
Radiation
Tumors
Recovery
Comet Assay
Radiation Tolerance
Fractionation
Plating
Heterografts
Nude Mice
DNA Repair
Small Interfering RNA
Inhibition (Psychology)

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Inhibition of NF-κB and DNA double-strand break repair by DMAPT sensitizes non-small-cell lung cancers to X-rays. / Estabrook, Neil C.; Chin-Sinex, Helen; Borgmann, Anthony J.; Dhaemers, Ryan M.; Shapiro, Ronald H.; Gilley, David; Huda, Nazmul; Crooks, Peter; Sweeney, Christopher; Mendonca, Marc.

In: Free Radical Biology and Medicine, Vol. 51, No. 12, 15.12.2011, p. 2249-2258.

Research output: Contribution to journalArticle

Estabrook, NC, Chin-Sinex, H, Borgmann, AJ, Dhaemers, RM, Shapiro, RH, Gilley, D, Huda, N, Crooks, P, Sweeney, C & Mendonca, M 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, vol. 51, no. 12, pp. 2249-2258. https://doi.org/10.1016/j.freeradbiomed.2011.09.029
Estabrook, Neil C. ; Chin-Sinex, Helen ; Borgmann, Anthony J. ; Dhaemers, Ryan M. ; Shapiro, Ronald H. ; Gilley, David ; Huda, Nazmul ; Crooks, Peter ; Sweeney, Christopher ; Mendonca, Marc. / Inhibition of NF-κB and DNA double-strand break repair by DMAPT sensitizes non-small-cell lung cancers to X-rays. In: Free Radical Biology and Medicine. 2011 ; Vol. 51, No. 12. pp. 2249-2258.
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