Parthenolide sensitizes cells to X-ray-induced cell killing through inhibition of NF-kappaB and split-dose repair.
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.
Mendonca
Marc S
MS
Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. mmendonc@iupui.edu
Chin-Sinex
Helen
H
Gomez-Millan
Jaime
J
Datzman
Nicholas
N
Hardacre
Michael
M
Comerford
Kathleen
K
Nakshatri
Harikrishna
H
Nye
Monica
M
Benjamin
Laura
L
Mehta
Sachin
S
Patino
Fatima
F
Sweeney
Christopher
C
D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000145:classification / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014965:X-Rays
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D012717:Sesquiterpenes; D014404:Tubulin; D016159:Tumor Suppressor Protein p53; C002669:parthenolide