Preliminary Study Of Anti-Cancer Effects And Mechanism Of Novel Dammarane Derivatives

Cancer has became one of the leading causes of death.Although the combined strategies of chemotherapy,surgery and radiotherapy increased the survival rate of cancer patients,the rapid proliferation and metastasis remained the major causes of death.Thus,the identification of new anti-cancer agents and the strategies based on the effective combinational approaches are necessarily developed.Substances derived from plants play an important role in the development of novel anti-cancer drugs.We have recently been interested in evaluating the anti-cancer activity of modified compounds isolated from P.ginseng.Ginseng is used in many cultures,especially in China and other Asian countries,for treatment and prevention of various diseases,including cancer.The ginsenosides are responsible for most of the pharmacological effects of ginseng and notoginseng.AD-2,one of ginsenosides,is a natural anti-cancer compound isolated from P.ginseng fruits,which can inhibit human cancer cell proliferation.In order to further improve the anti-cancer activities of AD-2,we synthesized a battery of AD-2 analogs by incorporating an extra amino group or chloroacetyl group at C-3-OH or C-12-OH.The cytotoxic effects of 1C,compound 5,AD-2,Rg3 and Mitomycin C were examined and compared on the survival of human cancer cell lines and normal human gastric epithelial cell line-GES-1(non-malignant).1C and compound 5 exhibited strong inhibition of cell viabilities on various cancer cell lines.The IC50 values of 1C and compound 5 for the cells ranged from 8.287 to 21.647μM and 7.54 to 25.91μM,which were significantly more potent than AD-2(ranged from 30.07 to 40.41μM),Rg3 and Mitomycin C.1C and compound 5 barely affected normal cells(GES-1).We investigate the cellular and molecular mechanisms of 1C and compound 5 as an anti-cancer agent.Firstly,1C triggered apoptosis via Bcl-2 family-mediated mitochondria pathway,down-regulated expression of mouse double minute 2(MDM2),up-regulated expression of p53 and stimulated reactive oxygen species(ROS)production.ROS scavenger N-acetylcysteine(NAC)can attenuate 1C-induce apoptosis.1C also inhibited the proliferation of LNCaP cells through inhibition on Wnt/β-catenin signalling pathway.Compound 5 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 compoundIn conclusion,1C and compound 5 show obvious anti-cancer activity based on inducing cell apoptosis by reactive oxygen species production,delaying cell cycle arrest and inhibiting Wnt/β-catenin signalling pathway.These findings demonstrate that 1C and compound 5 may provide leads as a potential agent for cancer therapy.