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

Marc Mendonca, Helen Chin-Sinex, Jaime Gomez-Millan, Nicholas Datzman, Michael Hardacre, Kathleen Comerford, Harikrishna Nakshatri, Monica Nye, Laura Benjamin, Sachin Mehta, Fatima Patino, Christopher Sweeney

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

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-κB-activated CGL1 cells. Treatment with 5 μM parthenolide for 48 to 72 h inhibited constitutive NF-κB 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 p21waf1/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.

Original languageEnglish
Pages (from-to)689-697
Number of pages9
JournalRadiation Research
Volume168
Issue number6
DOIs
StatePublished - Dec 2007

Fingerprint

X-radiation
X-Rays
dosage
apoptosis
cells
x rays
induction
interphase
Apoptosis
phosphorylation
S Phase
cytometry
radiation
chemotherapy
plating
parthenolide
therapy
Radiation
depletion
stabilization

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Radiology Nuclear Medicine and imaging
  • Biophysics
  • Radiation

Cite this

Mendonca, M., Chin-Sinex, H., Gomez-Millan, J., Datzman, N., Hardacre, M., Comerford, K., ... Sweeney, C. (2007). Parthenolide sensitizes cells to X-ray-induced cell killing through inhibition of NF-κB and split-dose repair. Radiation Research, 168(6), 689-697. https://doi.org/10.1667/RR1128.1

Parthenolide sensitizes cells to X-ray-induced cell killing through inhibition of NF-κB and split-dose repair. / Mendonca, Marc; Chin-Sinex, Helen; Gomez-Millan, Jaime; Datzman, Nicholas; Hardacre, Michael; Comerford, Kathleen; Nakshatri, Harikrishna; Nye, Monica; Benjamin, Laura; Mehta, Sachin; Patino, Fatima; Sweeney, Christopher.

In: Radiation Research, Vol. 168, No. 6, 12.2007, p. 689-697.

Research output: Contribution to journalArticle

Mendonca, M, Chin-Sinex, H, Gomez-Millan, J, Datzman, N, Hardacre, M, Comerford, K, Nakshatri, H, Nye, M, Benjamin, L, Mehta, S, Patino, F & Sweeney, C 2007, 'Parthenolide sensitizes cells to X-ray-induced cell killing through inhibition of NF-κB and split-dose repair', Radiation Research, vol. 168, no. 6, pp. 689-697. https://doi.org/10.1667/RR1128.1
Mendonca, Marc ; Chin-Sinex, Helen ; Gomez-Millan, Jaime ; Datzman, Nicholas ; Hardacre, Michael ; Comerford, Kathleen ; Nakshatri, Harikrishna ; Nye, Monica ; Benjamin, Laura ; Mehta, Sachin ; Patino, Fatima ; Sweeney, Christopher. / Parthenolide sensitizes cells to X-ray-induced cell killing through inhibition of NF-κB and split-dose repair. In: Radiation Research. 2007 ; Vol. 168, No. 6. pp. 689-697.
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