Parthenolide, a natural inhibitor of Nuclear Factor-kappaB, inhibits lung colonization of murine osteosarcoma cells.
PURPOSE: The transcription factor nuclear factor-kappaB (NF-kappaB) regulates the expression of several genes important for tumor metastasis and is constitutively active in the highly metastatic murine osteosarcoma cell line LM8. Parthenolide, a sesquiterpene lactone, was reported to inhibit the DNA binding of NF-kappaB. The purpose of this study is to investigate the usefulness of parthenolide as target for antimetastatic therapies. EXPERIMENTAL DESIGN: We examined the effect of parthenolide on metastasis-associated phenotypes in vitro and in murine experimental lung metastasis models by s.c. and i.v. inoculation of LM8 cells. RESULTS: We found that parthenolide strongly induced apoptosis and inhibited cell proliferation and the expression of vascular endothelial growth factor in vitro. In the in vivo metastasis models, parthenolide treatment suppressed lung metastasis when treatment was initiated concurrently with s.c. or i.v. inoculation of tumor cells, whereas lung metastasis was not reduced when parthenolide was given after the homing of tumor cells. The growth of s.c. tumors that developed at the inoculation site was not suppressed by parthenolide. We also found that the genetic inhibition of NF-kappaB activity by expressing mutant IkappaBalpha suppressed lung metastasis in vivo but not s.c. tumor growth. This supports our notion that the metastasis-preventing effect of parthenolide is mediated at least in part by inhibition of NF-kappaB activity. CONCLUSIONS: These findings suggested that NF-kappaB is a potential molecular target for designing specific prophylactic interventions against distant metastasis and that parthenolide is a hopeful candidate for an antimetastatic drug.