Novel Ginsenoside AD-1Inhibits Lung Cancer And The Possible Mechanisms Of Action

AIM:The global burden of lung cancer continues to increase largely. The large number of cases and poor survival rates under current therapies necessitate the search for novel drugs for lung cancer. Panax ginseng has been used as a medicinal plant in China for thousands of years. Low toxicity and positive studies in concomitant use with other chemotherapeutic agents is promising. In given the lack of effective therapies for lung cancer, and the high incidence of the disease, we wanted to determine whether AD-1could represent a novel therapeutic agent for lung cancer. To test our hypothesis, we evaluated the anti-lung cancer effects of the compound in vitro and in vivo, and accomplished preliminary studies elucidating its mechanisms of action.METHODS:In vivo, the A549and H292xenograft models were established by subcutaneous implantation of A549and H292cells into athymic nude mice. Tumor bearing mice were given p.o. with Rg3and AD-1at different doses every day respectively. Tumor size was determined every two days. Immunohistochemistry was performed to detect the expression of VEGF, MMP-9and CD34in tumor tissue.In vitro, the effects of the test compound on human cancer cell growth, expressed as the percentage of cell survival, were determined using the MTT assay. The effects of AD-1on the cell cycle distribution and stages of apoptosis were detected by use of flow cytometry. Cells that were positive for AnnexinV-FITC alone (early apoptosis) and AnnexinV-FITC and PI (late apoptosis) were counted. In addition, the potential mechanisms underlying the effects of AD-1were investigated. The expression levels of various proteins and phosphorylation of p38, ERK after24h exposure to different concentrations of AD-1were assessed by western blots.RESULTS:AD-1showed a dose-dependent inhibitory effect on the growth of xenograft tumor, the inhibitory effect was significant at high doses.AD-1significantly inhibited A549xenograft tumor growth by27%and42%at doses of20and40mg/kg. Besides, AD-1(10,20,40mg/kg) decreased the levels of VEGF, MMP-9and CD34.In vitro, AD-1exerted potent effects against various cell lines, leading to significant decreases in cell viability, especially in the malignant cells. AD-1had the lowest IC50values (in the low μM range) in three human lung cancer cell lines compared with other ginsenosides tested. For both A549and H292cells, AD-1induced cell cycle arrest in the G1phase and apoptosis in a dose-dependent manner. Further, AD-1increased expression of p21, p27, Bax in the two cell lines. The compound also reduced expression of cyclinDl, cyclinE, MDM-2, Bcl-2, which correlated with the cell cycle arrest in G1and cell apoptosis. Moreover, anti-cancer activity mediated by AD-1was associated with increased level of phosphorylated p38and ERK, which were important for cell growth, survival and apoptosis.CONCLUSIONS:AD-1could inhibit the growth of lung cancer both in vitro and in vivo, moreover, anti-cancer activity mediated by AD-1was associated with increased level of phosphorylated p38and ERK.