Reduction of Adipose Tissue Mass by the Angiogenesis Inhibitor ALS-L1023 from Melissa officinalis.

It has been suggested that angiogenesis modulates adipogenesis and obesity. This study was undertaken to determine whether ALS-L1023 (ALS) prepared by a two-step organic solvent fractionation from Melissa leaves, which exhibits antiangiogenic activity, can regulate adipose tissue growth. The effects of ALS on angiogenesis and extracellular matrix remodeling were measured using in vitro assays. The effects of ALS on adipose tissue growth were investigated in high fat diet-induced obese mice. ALS inhibited VEGF- and bFGF-induced endothelial cell proliferation and suppressed matrix metalloproteinase (MMP) activity in vitro. Compared to obese control mice, administration of ALS to obese mice reduced body weight gain, adipose tissue mass and adipocyte size without affecting appetite. ALS treatment decreased blood vessel density and MMP activity in adipose tissues. ALS reduced the mRNA levels of angiogenic factors (VEGF-A and FGF-2) and MMPs (MMP-2 and MMP-9), whereas ALS increased the mRNA levels of angiogenic inhibitors (TSP-1, TIMP-1, and TIMP-2) in adipose tissues. The protein levels of VEGF, MMP-2 and MMP-9 were also decreased by ALS in adipose tissue. Metabolic changes in plasma lipids, liver triglycerides, and hepatic expression of fatty acid oxidation genes occurred during ALS-induced weight loss. These results suggest that ALS, which has antiangiogenic and MMP inhibitory activities, reduces adipose tissue mass in nutritionally obese mice, demonstrating that adipose tissue growth can be regulated by angiogenesis inhibitors.

Neolignans from Saururus chinensis inhibit PC-3 prostate cancer cell growth via apoptosis and senescence-like mechanisms.

This study investigated the anticancer activity and related mechanisms of neolignans, especially threo, erythro-manassantin A (compound 2), which are isolated from Saururus chinensis, in PC-3 cells. Compound 2 strongly inhibited the proliferation of PC-3 cells in a dose-dependent manner. Different cell morphologies were observed depending on the concentration of compound 2, which suggested different growth inhibitory mechanisms. DNA flow cytometry indicated that both low and high concentrations of compound 2 induced the arrest of PC-3 cells in G1 phase. Western blot analyses showed that hyperphosphorylated Rb and E2F-1 were decreased, whereas hypophosphorylated Rb was increased. The cells treated with compound 2 at 200 ng/ml showed shrinkage morphologically, and the staining of annexin V-FITC revealed apoptotic cell death of these cells. The induction of apoptosis was accompanied by the cleavage of caspase-3, -8, and -9, as well as the downregulation of the Bcl-2 and the upregulation of Bax. By contrast, at low compound 2 concentration (1 ng/ml), the cells arrested in G1 showed characteristic changes in morphology, such as an enlarged, flattened cell shape; the majority strongly expressed SA-beta-galactosidase activity. The number of cells undergoing apoptosis was negligible, and no poly(ADP-ribose) polymerase (PARP) cleavage was observed. The increase of p21 was noticed. However, it appeared to be transient rather than sustained. The protein p27 may be important for maintaining the senescence machinery induced by compound 2 because p27 expression was increased at low concentration compared with that at high concentration. In conclusion, compound 2 showed a significant growth inhibitory effect in PC-3 cells via two different mechanisms, i.e., apoptosis at high concentration and senescence at low concentration.

Cytotoxicity of neolignans identified in Saururus chinensis towards human cancer cell lines.

The cytotoxicity of compounds derived from the aerial parts of Saururus chinensis towards 24 cancer model and six normal cell lines was examined by MTT assay and compared with those of the anticancer agents cisplatin and doxorubicin. The active principles were characterized as the neolignans manassantin A, and its erythro, erythro- and threo, erythro-epimers by spectroscopic analysis. Manassantin A was isolated from S. chinensis as a new cytotoxic principle. Its two epimers were isolated for the first time in nature. The neolignans were more active than cisplatin and doxorubicin, with IC50 values of the neolignans, cisplatin, and doxorubicin against SK-Hep-1, PC-3, DU-145, BT-20, SK-BR-3, T-47D, Hela, T98G, and SK-MEL-28 cancer cell lines, in the ranges 0.018-0.423, 1.175-7.922, and 0.131- >50 microg/mL, respectively. Manassantin A and its threo, erythro-epimer were equicytotoxic towards model cancer cell lines. threo, erythro-Manassantin A was more active than erythro, erythro-manassantin A. Additionally, these three neolignans (IC50 > 10 microg/mL) had very low cytotoxicity towards six normal cell lines, whereas cisplatin (IC50 2.846-0.825 microg/mL) and doxorubicin (IC50 5.222-0.008 microg/mL) exhibited potent cytotoxic effects. Structure-activity relationships indicate that the hydroxy moiety appears to be essential for cytotoxicity. These neolignans merit further study as potential anticancer agents or as leads.