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1 April 2009 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 S. Mendonca
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Abstract

Watson, C. N., Miller, D. A., Chin-Sinex, H., Losch, A. C., Hughes, W., Sweeney, C. and Mendonca, M. S. Suppression of NF-κB Activity by Parthenolide Induces X-Ray Sensitivity through Inhibition of Split-Dose Repair in TP53 Null Prostate Cancer Cells. Radiat. Res. 171, 389–396 (2009).

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.

Christopher Watson, Douglas A. Miller, Helen Chin-Sinex, Adam Losch, William Hughes, Christopher Sweeney, and Marc S. Mendonca "Suppression of NF-κB Activity by Parthenolide Induces X-Ray Sensitivity through Inhibition of Split-Dose Repair in TP53 Null Prostate Cancer Cells," Radiation Research 171(4), 389-396, (1 April 2009). https://doi.org/10.1667/RR1394.1
Received: 12 March 2008; Accepted: 1 December 2008; Published: 1 April 2009
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