The Inhibitory Effect And Mechanism Of PGG Combined With 5-fU On HepG2 Cells

The fruit of Terminalia chebula Retz is known as the "king of medicines" in Tibetan medicine and Mongolian medicine.It has rich chemical constituents and pharmacological activities.It is frequently used in treatment of various diseases.Pentagalloyl glucose(PGG)is a natural polyphenol compound found in the fruit of T.chebula and other plants.It has been reported that PGG has anti-cancer activity.However,there are few studies on the anti-hepatocarcinogenic activity of PGG and the mechanism of action is not clear.The combination of natural products and chemotherapeutics is now emerging as a research hotspot.The combination reduces the concentration of conventional chemotherapeutic drugs.Therefore,the purpose of present study was to investigate the inhibition and mechanism of PGG on HepG2 cell and explore the effect of combination PGG with clinical chemotherapeutic 5-FU on Hep G2.It provides a scientific basis for the development of Mongolian medicine resources and the clinical application of natural anticancer compounds.Using modern chromatographic and spectroscopic technologies,6 compounds were isolated and identified from the fruit of T.chebula as: orientin(1);corilagin(2);chebulinic acid(3);pentagalloyl glucose(4);1,3,6-tri-O-galloyl-?-D-glucopyranose(5);11,12-dimethylchebulate(6).Using molecular biology and cell biology research techniques,it was found that PGG inhibited the proliferation of HepG2 cells in dose and time-dependent manners.PGG induced down-regulation of Bcl-2,Bcl-x/l,XIAP,p62,PI3 K,Akt and p-Akt,caused up-regulated expression of Bax,AIF,Atg13 and Atg14.Therefore,PGG induced apoptosis and autophagy and inhibited the PI3K/Akt signaling pathway.PGG inhibited the invasion and migration of HepG2 cells.Combination of PGG and 5-FU has a synergistic effect in a wide range,such as inhibiting the growth of Hep G2 cells in a concentration-dependent manner,up-regulating the rate of Bax/Bcl-2,activating caspase-3 and caspase-9,increasing the expression of P27 and cyclingB1,decreasing the expression of cyclingE1 and Akt,inducing HepG2 cell apoptosis and decreasing mitochondrial membrane potential,and resulting in G1 arrest;Combination of PGG and 5-FU inhibited invasion and migration of HepG2 cells.The combination of PGG and 5-FU reduced the expression of MDR1 and LRP1,and has the potential for reversing 5-FU resistance.In conclusion,PGG,bioactive chemical constituents of T.chebula furit,showed anti-hepatoma activity,and when combined with 5-FU,it enhanced the sensitivity of Hep G2 cells to 5-FU,reduced the amount of 5-FU,which is of great significance in clinical practice.