Parthenolide Sensitizes Cells to X-Ray-Induced Cell Killing through Inhibition of NF-κB and Split-Dose Repair

Abstract

Mendonca, M. S., Chin-Sinex, H., Gomez-Millan, J., Datzman, N., Hardacre, M., Comerford, K., Nakshatri, H., Nye, M., Benjamin, L., Mehta, S., Patino, F. and Sweeney, C. Parthenolide Sensitizes Cells to X-Ray-Induced Cell Killing through Inhibition of NF-κB and Split-Dose Repair. Radiat. Res. 168, 689–697 (2007).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.