4-XL-PPD, a novel ginsenoside derivative, as potential therapeutic agents for gastric cancer shows anti-cancer activity via inducing cell apoptosis medicated generation of reactive oxygen species and inhibiting migratory and invasive.

(20R)-Dammarane-3ß, 12ß, 20, 25-tetrol (25-OH-PPD) is a ginsenoside isolated from Panax ginseng (C. A. Meyer). Previous research shows that the compound exhibits anti-cancer activities on many human cancer cell lines. In an attempt to enhance 25-OH-PPD activity, some derivatives were synthesized. Through screening of the derivative compounds for anti-cancer activity against gastric carcinoma cells, 12ß-O-(L-Chloracetyl)-dammar-20(22)-ene-3ß, 25-diol (4-XL-PPD) was selected as a strong anti-cancer agent. In this study, the anti-cancer mechanisms of 4-XL-PPD were investigated. The results showed that compound 4-XL-PPD resulted in a concentration-dependent inhibition of cells viability in gastric cancer cells, without affecting the viability of normal cell (human gastric epithelial cell line-GES-1). In BGC-803 cancer cells, 4-XL-PPD triggered apoptosis, and stimulated reactive oxygen species production. Apoptosis can be attenuated by the reactive oxygen species scavenger N-acetylcysteine. Meantime, 4-XL-PPD effectively suppressed the migratory and invasive capabilities of BGC-803 cancer cell and inhibited the expression levels of proteins associated with migratory and invasive capabilities (MMP-2, MMP-9, E-cadherin and CD34). All the results suggest that 4-XL-PPD exhibited remarkable anticancer activity base on inducing apoptosis via generating reactive oxygen species and inhibiting migratory and invasive, which support development of 4-XL-PPD as a potential agent for cancer therapy.

Semi-synthesis and anti-tumor activity of novel 25-OCH3-PPD derivatives incorporating aromatic moiety.

Previously we have reported that 25-OCH3-PPD could suppress the reproduction of cancer cells and cause apoptosis without obvious toxicity. Herein, we aimed to enhance its bioactivity by introducing aromatic groups to its dammarane-type skeleton. These synthesized derivatives were tested for their inhibitory activities against five cancer cell lines. Of them, compounds 3a, 14a and 18a had the strongest antiproliferative activities against tumor cells (IC50 < 15 µM, 5-fold to 10-fold increases than 25-OCH3-PPD). Especially compound 14a displayed the most potent activity against DU145, MCF-7 and HepG2 cells (IC50 = 6.7 ±â€¯0.8, 4.3 ±â€¯0.8 and 5.8 ±â€¯0.6 µM, respectively). Structure-activity relationships demonstrated that having aromatic ester at the C3 position could improve the bioactivity. The data provided new insights into exploring novel antiproliferative lead compounds.

Anticancer activity and potential mechanisms of 1C, a ginseng saponin derivative, on prostate cancer cells.

BACKGROUND: AD-2 (20(R)-dammarane-3b, 12b, 20, 25-tetrol; 25-OH-PPD) is a ginsenoside and isolated from Panax ginseng, showing anticancer activity against extensive human cancer cell lines. In this study, effects and mechanisms of 1C ((20R)-3b-O-(L-alanyl)-dammarane-12b, 20, 25-triol), a modified version of AD-2, were evaluated for its development as a novel anticancer drug. METHODS: MTT assay was performed to evaluate cell cytotoxic activity. Cell cycle and levels of reactive oxygen species (ROS) were determined using flow cytometry analysis. Western blotting was employed to analyze signaling pathways. RESULTS: 1C concentration-dependently reduces prostate cancer cell viability without affecting normal human gastric epithelial cell line-1 viability. In LNCaP prostate cancer cells, 1C triggered apoptosis via Bcl-2 family-mediated mitochondria pathway, downregulated expression of mouse double minute 2, upregulated expression of p53 and stimulated ROS production. ROS scavenger, N-acetylcysteine, can attenuate 1C-induced apoptosis. 1C also inhibited the proliferation of LNCaP cells through inhibition on Wnt/ß-catenin signaling pathway. CONCLUSION: 1C shows obvious anticancer activity based on inducing cell apoptosis by Bcl-2 family-mediated mitochondria pathway and ROS production, inhibiting Wnt/ß-catenin signaling pathway. These findings demonstrate that 1C may provide leads as a potential agent for cancer therapy.

Hair growth promotion effect of cedrol cream and its dermatopharmacokinetics.

Topical use of cedrol ethanol has been reported to have a beneficial effect on hair loss. However, the use of cedrol has been limited by application-related issues, such as poor water solubility and volatile features. Therefore, the present study developed a cream formulation of cedrol and evaluated various physicochemical parameters of the prepared cream. The optimized cedrol cream was selected after orthogonal tests and determined further. The dermatopharmacokinetics were studied to investigate the absorption difference between cedrol cream and cedrol ethanol after dermal application, and the concentrations of cedrol in skin were analysed by the gas chromatography-mass spectrometry (GC-MS) method. By comparison, the area under the curve (AUC0-24 h) of cedrol cream was almost three times higher than that of cedrol ethanol. Moreover, this study was undertaken to evaluate the hair growth promoting efficacy of cedrol cream in C57BL/6 mice and Wistar rats. Macroscopic assessment and alopecia score showed that C57BL/6 mice treated with cedrol cream showed a faster production of pigmentation and a higher score at different growth stages than other groups. The hair length of the cedrol cream-treated group was much longer than those of the cedrol ethanol and minoxidil groups. Histological analyses indicated that in the cedrol ethanol group, most follicles of the C57BL/6 mice were in the catagen phase, whereas nearly 83% of hair follicles in the cedrol cream group remained in the anagen phase. Taken together, our data strongly suggest that the cream formulation of cedrol has a stronger hair growth promotion effect, gave no irritation and was safe for topical administration.

One-pot synthesis, anti-tumor evaluation and structure-activity relationships of novel 25-OCH3-PPD derivatives.

Based on the fact that 25-OCH3-PPD, a natural ginsengenin isolated from the leaves of Panax ginseng, is a promising lead compound, novel 25-OCH3-PPD derivatives were synthesized to find more potent anti-tumor agents by a simple and facile synthetic method. These derivatives were classified into three types and screened for their cytotoxic activities against seven human cancer cell lines. Compared with 25-OCH3-PPD, compounds a5, a7, b5 and b7 exhibited higher anti-tumor activities on all tested cell lines with almost 5-fold to 15-fold increases. In particular, compound a7 showed the greatest cytotoxic activity against α-2 cells (IC50 = 2.4 ± 0.4 µM). The preliminary study on the mechanisms indicated that compound a7 could induce α-2 cell apoptosis. Structure-activity relationships demonstrated that the carbon-carbon double bond at the C-20 position could enhance the antiproliferative activity. In conclusion, the novel derivatives a5, a7, b5 and b7 could be further studied as potential candidates for the treatment of cancer. This research provides a theoretical reference for the exploration of new antiproliferative agents.

12-Chloracetyl-PPD, a novel dammarane derivative, shows anti-cancer activity via delay the progression of cell cycle G2/M phase and reactive oxygen species-mediate cell apoptosis.

(20R)-Dammarane-3ß, 12ß, 20, 25-tetrol (25-OH-PPD) is a ginsenoside isolated from Panax ginseng (C. A. Meyer). This compound exhibits anti-cancer activities on many human cancer cell lines. In this study, we investigated anti-cancer mechanisms of 12ß-O-(L-Chloracetyl)-dammar-20(22)-ene-3ß,25-diol(12-Chloracetyl-PPD), a modified 25-OH-PPD. We found that compound 12-Chloracetyl-PPD resulted in a concentration-dependent inhibition of viability in prostate, breast, and gastric cancer cells, without affecting the viability of normal cell (human gastric epithelial cell line-GES-1, hair follicle dermal papilla cell line-HHDPC and rat myocardial cell line-H9C2). In MDA-MB-435 and C4-2B cancer cells, 12-Chloracetyl-PPD induced G2/M cell cycle arrest, down-regulated mouse double minute 2 (MDM2) expression, up-regulated p53 expression, triggered apoptosis, and stimulated reactive oxygen species production. Apoptosis can be attenuated by the reactive oxygen species scavenger N-acetylcysteine. Our results suggested that compound 12-Chloracetyl-PPD showed obvious anti-cancer activity based on delaying cell cycle arrest and inducing cell apoptosis by reactive oxygen species production, which supported development of 12-Chloracetyl-PPD as a potential agent for cancer chemotherapy.

Hair growth promoting activity of cedrol isolated from the leaves of Platycladus orientalis.

Platycladus orientalis (L.) Franco is traditionally known to potentiate hair growth promotion. However, there has been no report on its main active ingredient responsible for the hair growth activity. In the current work, cedrol as a major constituent from P. orientalis was evaluated for its potential on hair growth in vivo. Different concentrations of cedrol (10, 20 and 30mg/mL) were applied topically over the shaved skin of C57BL/6 mice and monitored for 21days. Results indicated that cedrol significantly promoted hair growth in a dose-dependent manner, particularly for the female mice. Both male and female mice groups treated with 30mg/mL cedrol required shorter time than the blank control and 2% minoxidil groups at different growth stages. Compared with the blank control (8.87mm) and 2% minoxidil (9.94mm) groups at 21days, the hair length of female mice treated with 30mg/mL cedrol showed a remarkable increase with the value of 11.07mm. Hair in male and female mice groups treated with 30mg/mL cedrol was heavier than the 2% minoxidil (38.2 and 35.9mg, respectively) groups with the weight of 42.6 and 45.2mg, respectively. Further observation of the hair follicle demonstrated that cedrol exerted a remarkable effect on the hair follicle length. These findings suggested that cedrol may be the main active ingredient of P. orientalis and have the potential of becoming a new hair growth promoter.

Novel 25-hydroxyprotopanaxadiol derivatives incorporating chloroacetyl chloride and their anti-tumor evaluation.

In the current work, 12 novel 25-hydroxyprotopanaxadiol (25-OH-PPD) derivatives were synthesized by reacting with chloroacetyl chloride. And their in vitro antitumor activities were evaluated on six human tumor cell lines by MTT assay. The results demonstrated that, as compared with 25-OH-PPD, compounds 4, 6 and 7 exhibited higher cytotoxic activity on all tested cell lines. Of them, compound 4 showed strongly inhibition against MCF-7, HCT-116 and Lovo cells with IC50 values of 1.7, 1.6 and 2.1 µM, respectively. The IC50 values of compound 6 against HCT-116 and 7 against MCF-7 were the lowest (1.2 and 1.6 µM, respectively). It was also noted that compound 4 showed a 20- to 100-fold greater growth inhibition than ginsenoside-Rg3 (an anti-cancer regular drug in China). In conclusion, the data revealed that compounds 4, 6 and 7 were potential candidates for anti-tumor treatment and may be useful for the development of novel antiproliferative agents.