The clinical applications of Rhizoma paridis in
traditional Chinese medicine are well known. However, the therapeutic potential of Rhizoma paridis and its active component such as Paris saponin I (
polyphyllin D) and Paris saponin II (PSII) (formosanin C) in
cancer treatments have not yet been fully explored. Recent studies have demonstrated that PSII and chemoagents exhibit comparable inhibitory affects against human
ovarian cancer cell growth. Since NF-κB, a ubiquitous
transcription factor that plays an important role in
cancer biology, is often associated with gynecological
cancers, in the present study, we evaluated the possibility that PSII modulates NF-κB activity and
VEGF-mediated angiogenesis and elucidated the molecular mechanisms underlying such effects. We assessed the effects of PSII on NF-κB activity in SKOV3
tumor cells and on
tumor cell induced-angiogenesis using standardized angiogenesis in vitro, ex vivo and in vivo assays, western blot analysis and
kinase assay. We also assessed the effect of the super-engineered repressor of IĸBα and its effect, in combination with PSII treatment on
tumor growth and angiogenesis in xenograft athymic mouse models of
ovarian cancer (SKOV3 and SKOV3/mutant IĸBα cells) using color Doppler ultrasound and traditional immunohistochemistry. We showed that PSII suppressed NF-κB activation as a result of the reduction in IKKβ
kinase activity on its substrate IκBα and the expression of IKKβ. Compromising NF-κB activation reduced the expression of NF-κB-downstream targets such as
VEGF, Bcl-2 and Bcl-xL. Such inhibitory effects at molecular levels appear to compromise
tumor growth and angiogenesis. Most importantly, the combination of PSII treatment and constitutive repression of IĸBα activity exhibited marked inhibitory effects against human
ovarian cancer cell growth in a xenograft mouse model of
ovarian cancer. For the first time, we provide evidence showing that PSII potently inhibits angiogenesis and the growth of human
ovarian cancer by suppressing NF-κB signaling.