Cell context-dependent activities of parthenolide in primary and metastatic melanoma cells.

BACKGROUND AND
PURPOSE: Growing evidence implicates NF-kappaB as an important contributor to metastasis and increased chemoresistance of melanoma. Here, we report the effects of parthenolide on either untreated, cisplatin- or TNFalpha-treated melanoma cell lines A375, 1205Lu and WM793, exhibiting different levels of constitutive NF-kappaB activity. EXPERIMENTAL APPROACH: Electrophoretic mobility shift assay was used to assess changes in NF-kappaB activity, and real-time PCR to evaluate expression of NF-kappaB-regulated genes. Cell cycle arrest and apoptosis were assessed by flow cytometry. Cell death was also visualized by fluorescence microscopy. Migration was determined by scratch assay and invasiveness by Matrigel assay. KEY
RESULTS: Parthenolide suppressed both constitutive and induced NF-kappaB activity in melanoma cells. This was accompanied by down-regulation of cancer-related genes, with NF-kappaB-binding sites in their promoters, including: Bcl-X(L), survivin, cyclin D1, interleukin 8 and matrix metalloproteinase 9. When the various effects of 6 microM parthenolide were compared, apoptosis associated with loss of mitochondrial membrane potential was most efficiently induced in 1205Lu cells, cell cycle arrest in G(0)/G(1) phase was observed in WM793 cells, and high metastatic potential was markedly reduced in A375 cells. These findings not only reflected differences between melanoma cell lines in basal expression of NF-kappaB-regulated genes, but also suggested other parthenolide targets involved in cell cycle progression, migration, invasiveness and survival.
CONCLUSIONS: Inhibition of constitutive and therapeutically induced NF-kappaB pathway by parthenolide might be useful in the treatment of melanoma, although the diversity of changes induced in melanoma cells with different genetic backgrounds indicate context-dependent poly-pharmacological properties of this compound.