Suppression of NF-κB activity by parthenolide induces x-ray sensitivity through inhibition of split-dose repair in TP53 null prostate cancer Cells

Christopher Watson, Douglas A. Miller, Helen Chin-Sinex, Adam Losch, William Hughes, Christopher Sweeney, Marc Mendonca

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

We have shown that parthenolide, a sesquiterpene lactone, is a radiation sensitizer for human CGL1 hybrid cells that have constitutively activated NF-κB and wild-type p53. Since many malignant cells have nonfunctional p53, we investigated whether parthenolide could alter the X-ray sensitivity of PC-3 prostate cancer cells, a p53 null cell line with constitutively activated NF-κB. The addition of 5 μM parthenolide induced non-apoptotic cell death, inhibited PC-3 proliferation, and increased the population doubling time from 23 ± 1 h to 49 ± 4 h. Parthenolide also inhibited constitutive and radiation-induced NF-κB binding activity and enhanced the X-ray sensitivity of these p53 null PC-3 cells by a dose modification factor of 1.7. Cell cycle analysis of PC-3 cells treated with parthenolide showed only small alterations in G1 and G2/M cells, and these appeared to be insufficient to explain the observed radiosensitization. Split-dose studies using clinically relevant 2- and 4-Gy fractions demonstrated that parthenolide completely inhibited split-dose repair in PC-3 cells. We hypothesized that inhibition of NF-κB activity by parthenolide was responsible for the observed X-ray sensitization and inhibition of split-dose repair. To test this hypothesis, we knocked down the expression of NF-κB p65 protein, an active component of NF-κB in both PC-3 and CGL1 cells, by siRNA. Inhibition of NF-κB activity by knockdown of p65 increased radiation sensitivity and completely inhibited split-dose repair in both cell lines in a nearly identical manner as parthenolide treatment alone. Treating p65-depleted PC-3 cells with 5 μM parthenolide did not further increase their radiation sensitivity or the inhibition of split-dose repair. We propose that the suppression of radiation-induced NF-κB activity by parthenolide leads to X-ray sensitization through inhibition of split-dose repair in p53 null PC-3 prostate cancer cells.

Original languageEnglish
Pages (from-to)389-396
Number of pages8
JournalRadiation Research
Volume171
Issue number4
DOIs
StatePublished - Apr 2009

Fingerprint

Prostatic Neoplasms
cancer
X-Rays
retarding
dosage
cells
x rays
radiation
cultured cells
Radiation Tolerance
parthenolide
Radiation
Radiation-Sensitizing Agents
Cell Line
Null Lymphocytes
death
Sesquiterpenes
Hybrid Cells
Lactones
Small Interfering RNA

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Biophysics
  • Radiation

Cite this

Suppression of NF-κB activity by parthenolide induces x-ray sensitivity through inhibition of split-dose repair in TP53 null prostate cancer Cells. / Watson, Christopher; Miller, Douglas A.; Chin-Sinex, Helen; Losch, Adam; Hughes, William; Sweeney, Christopher; Mendonca, Marc.

In: Radiation Research, Vol. 171, No. 4, 04.2009, p. 389-396.

Research output: Contribution to journalArticle

Watson, Christopher ; Miller, Douglas A. ; Chin-Sinex, Helen ; Losch, Adam ; Hughes, William ; Sweeney, Christopher ; Mendonca, Marc. / Suppression of NF-κB activity by parthenolide induces x-ray sensitivity through inhibition of split-dose repair in TP53 null prostate cancer Cells. In: Radiation Research. 2009 ; Vol. 171, No. 4. pp. 389-396.
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