Parthenolide sensitizes cells to X-ray-induced cell killing through inhibition of NF-kappaB and split-dose repair

Radiat Res. 2007 Dec;168(6):689-97. doi: 10.1667/RR1128.1.


Human cancers have multiple alterations in cell signaling pathways that promote resistance to cytotoxic therapy such as X rays. Parthenolide is a sesquiterpene lactone that has been shown to inhibit several pro-survival cell signaling pathways, induce apoptosis, and enhance chemotherapy-induced cell killing. We investigated whether parthenolide would enhance X-ray-induced cell killing in radiation resistant, NF-kappaB-activated CGL1 cells. Treatment with 5 microM parthenolide for 48 to 72 h inhibited constitutive NF-kappaB binding and cell growth, reduced plating efficiency, and induced apoptosis through stabilization of p53 (TP53), induction of the pro-apoptosis protein BAX, and phosphorylation of BID. Parthenolide also enhanced radiation-induced cell killing, increasing the X-ray sensitivity of CGL1 cells by a dose modification factor of 1.6. Flow cytometry revealed that parthenolide reduced the percentage of X-ray-resistant S-phase cells due to induction of p21 waf1/cip1 (CDKN1A) and the onset of G1/S and G2/M blocks, but depletion of radioresistant S-phase cells does not explain the observed X-ray sensitization. Further studies demonstrated that the enhancement of X-ray-induced cell killing by parthenolide is due to inhibition of split-dose repair.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Apoptosis / drug effects*
  • Apoptosis / radiation effects*
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Humans
  • NF-kappa B / metabolism*
  • Protein Binding
  • Proto-Oncogene Proteins c-bcl-2 / classification
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Sesquiterpenes / pharmacology*
  • Tubulin / metabolism
  • Tumor Suppressor Protein p53 / metabolism
  • X-Rays*


  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • NF-kappa B
  • Proto-Oncogene Proteins c-bcl-2
  • Sesquiterpenes
  • Tubulin
  • Tumor Suppressor Protein p53
  • parthenolide