Parthenolide (PN) is the main
sesquiterpene lactone found in feverfew with potent anti-inflammatory function. The anticancer property of PN has been demonstrated in both in vitro cell culture and in vivo animal model, while the molecular mechanisms remain to be further elucidated. In the present study, we evaluated the involvement of nuclear
transcription factor-kappaB (
NF-kappaB) and
c-Jun N-terminal kinase (JNK) in the anticancer activity of PN by examining the sensitization effect of PN on
tumor necrosis factor (
TNF)-alpha-induced apoptosis in human
cancer cells. Pre-treatment with PN greatly sensitized various human
cancer cells to
TNF-alpha-induced apoptosis. Such sensitization is closely associated with the inhibitory effect of PN on
TNF-alpha-mediated
NF-kappaB activation. Our study revealed a new mechanism that PN inhibits
TNF-alpha-mediated
NF-kappaB activation via disrupting the recruitment of the IkappaB
kinases (IKK) complex to
TNF receptor, which then blocked the subsequent signaling events including IKK
kinase activation,
IkappaBalpha degradation, p65 nuclear translocation,
DNA binding and transactivation. Moreover, PN also markedly enhanced and sustained
TNF-alpha-mediated JNK activation. A specific JNK inhibitor (
SP600125), as well as over-expression of dominant-negative forms of JNK1 and JNK2 abolished the sensitization effect of PN on
TNF-alpha-induced apoptosis. It is thus believed that suppressed
NF-kappaB activation and sustained JNK activation contribute to the sensitization effect of PN to
TNF-alpha-mediated cell death in human
cancer cells.