Paris Saponin II suppresses the growth of human ovarian cancer xenografts via modulating VEGF-mediated angiogenesis and tumor cell migration.

PURPOSE: Paris Saponin II (PSII) is an active component of Rhizoma Paridis-an essential ingredient in traditional Chinese herbal medicines. PSII can induce cytotoxic effects in cancer cells and inhibit ovarian cancer growth. Since pathological angiogenesis (henceforth, angiogenesis) is often associated with gynecological cancers, here, we investigated whether PSII renders effects on angiogenesis and examined possible molecular mechanisms underlying the effects of PSII. METHODS: The effects of PSII on the biofunctions of endothelial cells (EC), the crucial components of blood vessels, were examined by standardized angiogenesis in vitro and ex vivo assays, Western blot analysis, ELISA, and kinase assay. Angiogenesis in a xenograft mouse model of ovarian cancer was evaluated by color Doppler ultrasound and immunohistochemistry. RESULTS: PSII exerted marked inhibitory effect on the growth of VEGF-stimulated human umbilical vein endothelial cells in a dose-time-dependent manner, inhibited cell's motility, and interfered with tubulogenesis. PSII also blocked microvessel outgrowth in a rat aortic ring assay and compromised angiogenesis in a mouse model of ovarian carcinoma using either SKOV3 or HOC-7 cell lines. VEGF levels in PSII-treated EC and tumor cells were reduced. In EC, PSII blocked the activation of VEGFR2 in dose-dependent manner leading to the reduction of VEGF-induced phosphorylation on several intracellular pro-angiogenic kinase, including the extracellular signal-related kinase, Src family kinase, focal adhesion kinase, and AKT kinase. CONCLUSIONS: The results provided the first insight into the anti-angiogenesis properties of Saponin family in solid tumors and suggested a promising therapeutic potential of PSII in the ovarian cancer treatment.

Paris saponin II of Rhizoma Paridis--a novel inducer of apoptosis in human ovarian cancer cells.

Rhizoma Paridis (dried root and rhizome) has been an essential ingredient in traditional Chinese herbal medicine. In the past decade, active components of Rhizoma Paridis - the Paris saponins have emerged as promising anti-cancer agents. Among these saponins, polyphyllin D (Paris saponin (PS) I), has been extensively studied and proposed to be a potent antitumor agent. In this study, we continue to establish the efficacy and mechanisms underlying the cytotoxic effects of the steroidal PS members, namely formosanin C (PSII) in ovarian cancer treatment. We isolated PSII and evaluated its effects on a panel of ten human cell lines. Isolated PSII has potent inhibitory effects on the growth of tumor cells without deleterious effects to different normal cell types or benign neoplastic derived cells. While PSII, PSI, and etoposide are effective promoting agents for cell cycle arrest and apoptosis, PSII appeared to be marginally more potent than the later two in inhibiting SKOV3 cell growth. In PSII-treated SKOV3 cells, there was an elevation in proapoptotic elements including Bax, cytosolic cytochrome c, activated-caspase-3, and activated-caspase-9. The treatment also reduced extracellular signal-regulated kinase (ERK1/2) phosphorylation and anti-apoptotic Bcl-2 expression. We also assessed the antitumor efficacy of intraperitoneal administration of PSII in human SKOV3 ovarian cancer xenografts in athymic mice. PSII treatment significantly inhibited the growth of xenograft tumors relative to controls by 70% (p < 0.05). These findings demonstrated that, in addition to the unique selectivity against cancer cells, PSII is a potent antitumor molecule that may be developed as a cancer therapeutic agent.

The antitumoral effect of Paris Saponin I associated with the induction of apoptosis through the mitochondrial pathway.

Rhizoma Paridis, a traditional Chinese medicine, has shown promise in cancer prevention and therapy. In the present study, we isolated Paris Saponin I (PSI), an active component of Rhizoma paridis, and evaluated its effects on a panel of human cell lines and in a mouse model of human ovarian cancer to explore the mechanisms of its activity. PSI had more potent and selective cytotoxic effects on tumor cell lines than etoposide had, promoting dramatic G(2)-M phase arrest and apoptosis in SKOV3 cells in a time- and dose-dependent manner. Furthermore, PSI treatment increased levels of Bax, cytochrome c, activated caspase-3, active caspase-9, and cleaved poly(ADP-ribose) polymerase and decreased both Bcl-2 expression levels and extracellular signal-regulated kinase-1/2 activity. We also assessed the antitumor efficacy of i.p. and p.o. PSI administration in mice bearing SKOV3 tumors; both significantly inhibited the growth of SKOV3 cells in a subcutaneous xenograft mouse model (by 66% and 52%, respectively). These results indicate that PSI mediates its effects via mitochondrial apoptosis, mitogen-activated protein kinase pathways, and G(2)-M cell cycle arrest. Most important, the efficacy of PSI in xenografts when administered p.o. or i.p. suggests its clinical potential. Thus, PSI is a potent antitumor compound and should be developed as a natural agent for cancer therapy.