Paclitaxel sensitivity of breast cancer cells with constitutively active NF-κB is enhanced by IκBα super-repressor and parthenolide

The transcription factor nuclear factor-kappa B (NF-KB) regulates genes important for tumor invasion, metastasis and chemoresistance. Normally, NF-kappa B remains sequestered in an inactive state by cytoplasmic inhibitor-of-kappa B (I kappa B) proteins, NF-kappa B translocates to nucleus and activates gene expression upon exposure of cells to growth factors and cytokines, We and others have shown previously that NF-kappa B is constitutively active in a subset of breast cancers. In this study, we show that constitutive activation of NF-kappa B leads to overexpression of the antiapoptotic genes c-inhibitor of apoptosis 2 (c-IAP2) and manganese superoxide dismutase (Mn-SOD) in breast cancer cells, Furthermore, expression of the antiapoptotic tumor necrosis factor receptor associated factor 1 (TRAF1) and defender-against cell death (DAD-1) is regulated by NF-kappa B in certain breast cancer cells. We also demonstrate that NF-kappa B-inducible genes protect cancer cells against paclitaxel as MDA-MB-231 breast cancer cells modified to overexpress I kappa B alpha required lower concentrations of paclitaxel to arrest at the G2/M phase of the cell cycle and undergo apoptosis when compared to parental cells. The effect of NF-kappa B on paclitaxel-sensitivity appears to be specific to cancer cells because normal fibroblasts derived from embryos lacking p65 subunit of NF-kappa B and wild type littermate embryos were insensitive to paclitaxel-induced G2/M cell cycle arrest. Parthenolide, an active ingredient of herbal remedies such as feverfew (tanacetum parthenium), mimicked the effects of I kappa B alpha by inhibiting NF-kappa B DNA binding activity and Mn-SOD expression, and increasing paclitaxel-induced apoptosis of breast cancer cells. These results suggest that active ingredients of herbs with anti-inflammatory properties may be useful in increasing the sensitivity of cancers with constitutively active NF-kappa B to chemotherapeutic drugs.