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.

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Bone metastasis is a common and serious consequence of breast cancer. Bidirectional interaction between tumor cells and the bone marrow microenvironment drives a so-called 'vicious cycle' that promotes tumor cell malignancy and stimulates osteolysis. Targeting these interactions and pathways in the tumor-bone microenvironment has been an encouraging strategy for bone metastasis therapy. In the present study, we examined the effects of plumbagin on breast cancer bone metastasis. Our data indicated that plumbagin inhibited cancer cell migration and invasion, suppressed the expression of osteoclast-activating factors, altered the cancer cell induced RANKL/OPG ratio in osteoblasts, and blocked both cancer cell- and RANKL-stimulated osteoclastogenesis. In mouse model of bone metastasis, we further demonstrated that plumbagin significantly repressed breast cancer cell metastasis and osteolysis, inhibited cancer cell induced-osteoclastogenesis and the secretion of osteoclast-activating factors in vivo. At the molecular level, we found that plumbagin abrogated RANKL-induced NF-κB and MAPK pathways by blocking RANK association with TRAF6 in osteoclastogenesis, and by inhibiting the expression of osteoclast-activating factors through the suppression of NF-κB activity in breast cancer cells. Taken together, our data demonstrate that plumbagin inhibits breast tumor bone metastasis and osteolysis by modulating the tumor-bone microenvironment and that plumbagin may serve as a novel agent in the treatment of tumor bone metastasis.

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