Yanjun Zhang

Chemical study and medical application of saponins as anti-cancer agents.

Saponins are a group of naturally occurring plant glycosides, characterized by their strong foam-forming properties in aqueous solution. The presence of saponins has been reported in more than 100 families of plants out of which at least 150 kinds of natural saponins have been found to possess significant anti-cancer properties. There are more than 11 distinguished classes of saponins including dammaranes, tirucallanes, lupanes, hopanes, oleananes, taraxasteranes, ursanes, cycloartanes, lanostanes, cucurbitanes and steroids. Due to the great variability of their structures, saponins always display anti-tumorigenic effects through varieties of antitumor pathways. In addition, there are a large amount of saponins that still either remain to be trapped or studied in details by the medicinal chemists. This article reviews many such structures and their related chemistry along with the recent advances in understanding mechanism of action and structure-function relationships of saponins at the molecular and cellular levels. These aglycones have been described and their classification and distribution have been listed in the review. Some special saponins with strong antitumor effects have also been exhibited. Ginsenosides, belonging to dammaranes, have been found beneficial targeted on inhibition of tumor angiogenesis by suppressing its inducer in the endothelial cells of blood vessels, and then on prevention of adhering, invasion, and metastasis of tumor cells. Dioscin, one of the steroidal saponins, and its aglycone diosgenin also have been extensively studied on its antitumor effect by cell cycle arrest and apoptosis. Other important molecules discussed include oleanane saponins such as avicins, platycodons, saikosaponins, and soysaponins along with tubeimosides.

Antitumor and antimetastatic activities of Rhizoma Paridis saponins.

Rhizoma Paridis saponins (RPS) have been found to show strong antitumor activity. However, few studies have yet investigated its role on pulmonary metastasis treated with this herb. To investigate the molecular mechanisms related to metastasis, we studied RPS-treated T739 mice using histopathology, immunohistochemistry and reverse transcription polymerase chain reaction. Apoptosis was measured by TUNEL assay. As a result, RPS inhibited tumor growth by inducing apoptosis and upregulated the expression of TIMP-2 and down-regulated the level of MMP-2 and MMP-9. In conclusion, RPS is a potent anticancer agent that elicits programmed cell death and inhibits metastases in murine lung adenocarcinoma in vivo.

Characterization of steroidal saponins in saponin extract from Paris polyphylla by liquid chromatography tandem multi-stage mass spectrometry

Rhizoma Paridis saponins are bioactive steroidal saponins derived from Paris polyphylla. Optimization of the ionization process was performed with electrospray ionization tandem mass spectrometry in both positive and negative-ion modes. Negative-ion ESI was adopted for generation of the precursor deprotonated molecules to achieve the best ionization sensitivity for the analytes. Positive ionization was used to choose the most abundant fragment ion. Furthermore, according to the characteristic fragmentation behavior of known steroidal saponins isolated from this plant (polyphyllin D, formosanin C, gracillin, Paris H, Paris VII, and dioscin), 23 constituents were structurally characterized on the basis of their retention time and ESI analyses, including four pairs of naturally occurring isomers. Five of these 23 constituents were new compounds. The analytical method of LC–MSn in positive and negative-ion modes has been developed for the direct structural elucidation of steroid saponins of this kind in plant extracts.

Qualitative and quantitative determination of major saponins in Paris and Trillium by HPLC-ELSD and HPLC–MS/MS

High-performance liquid chromatographic (HPLC) with evaporative light scattering detection (ELSD) and HPLC with electrospray ionization multistage tandem mass spectrometry (HPLC-ESI-MS(n)) were used to identify and quantify steroid saponins in Paris and Trillium plants. The content of the known saponins such as Paris I, II, III, V, VI, VII, H, gracillin and protodioscin in Paris and Trillium plants was determined simultaneously using the developed HPLC-ELSD method. Furthermore, other 12 steroid saponins were identified by HPLC-ESI(+/-)-MS(n) detection. In the end, a developed analytical procedure was proved to be a reliable and rapid method for the quality control of Paris and Trillium plants. In addition, the alternative resources for Paris yunnanensis used as a traditional Chinese medicine were discovered according to the hierarchical clustering analysis of the saponin fraction of these plants.

Formosanin C-inhibited pulmonary metastasis through repression of matrix metalloproteinases on mouse lung adenocarcinoma.

Formosanin C (FC) isolated from Rhizoma Paridis, showed pro-apoptosis and immunoregulation with antitumor activity in cultured cells and animal systems. However, there is no report about its anti-metastatic effect on cancer cells. This research used the wound healing and the migration assay to detect the anti-invasive effect of FC on LA795 cells. Through the gelatin zymography assay and immunofluorescence analysis, FC showed suppression of enzyme activity of MMP-2 and MMP-9, and protein expression of MMP-1, -2, -3, -9 and -14 excreted from LA795 cells. Finally, FC exhibited much more effective inhibition of tumor growth and pulmonary metastasis in T739 mice than cisplatin did. Overall, the strong inhibition of MMP expression by FC might provide a potential therapeutic modality for lung tumors.

A new phenylpropanoid glycosides from Paris polyphylla var. yunnanensis.

A new phenylpropanoid glycosides, 2-feruloyl-O-alpha-D-glucopyranoyl-(1-->2)-3,6-O-feruloyl-beta-D-fructofuranoside, was isolated from the root of Paris polyphylla var. yunnanensis. The structure of the new glycoside was elucidated by spectroscopic methods. Cytotoxicity test showed that it has cytotoxic effect in a dose-dependent manner against the mice lung adenocarcinoma cell line (LA795).

Cyclophosphamide promotes pulmonary metastasis on mouse lung adenocarcinoma

Cyclophosphamide (CTX), as a common use of chemotherapeutic agent, has some side effects in clinical treatment. In our experiments, we studied CTX-treated T739 mice using histopathology, immunohistochemistry, reverse transcription polymerase chain reaction and Western blot for markers of proliferation, angiogenesis, tumor progression and distant metastasis. As a result, CTX increased the number and area of metastases and tumor embolus in lungs by effecting on the expression of matrix metalloproteinase-2, intercellular adhesion molecule-1 and tissue inhibitor of metalloproteinase-2. Taken together, it indicated that CTX enhanced the process of pulmonary metastasis by the synergistic effect of matrix-degrading proteases and adhesion proteins.

Identification of chemical constituents in Rhizoma Paridis Saponins and their oral administration in rat plasma by UPLC/Q-TOF/MS

On-line ultra-performance liquid chromatography (UPLC) coupled with diode-array detection (UPLC/DAD) and electrospray ionization quadrupole time-of-flight mass spectrometry (ESI-Q-TOF-MS) were used for separation, identification and structural analyses of saponins in Rhizoma Paridis saponins (RPS) and rat plasma after oral administration of RPS. Thirty steroidal saponins in RPS were identified by comparing their retention time, accurate mass measurement and positive and negative mass spectrometry data with that of reference compounds. The UPLC/Q-TOF-MS method was proved to be rapid and efficient in that 30 steroidal saponins, including three kinds of saponins (prototype, pennogenyl and diosgenyl saponins) were tentatively characterized within 6 min. After oral administration of RPS, 21 original saponins were absorbed in RPS-treated rat plasma. Our results indicated that UPLC/Q-TOF-MS is a rapid and effective tool for identification of a series of saponins at trace level.